CN106866733A

CN106866733A - Left-handed meptazinol prodrug and its production and use

Info

Publication number: CN106866733A
Application number: CN201611129691.0A
Authority: CN
Inventors: 向家宁; 徐雪松; 冯己
Original assignee: Kerry Corelle Biological Engineering (wuhan) Co Ltd
Current assignee: Kerry Corelle Biological Engineering (wuhan) Co Ltd; XWPharma Ltd
Priority date: 2015-12-11
Filing date: 2016-12-09
Publication date: 2017-06-20
Anticipated expiration: 2036-12-09
Also published as: CN106866733B

Abstract

The present invention proposes left-handed meptazinol prodrug and its production and use, wherein, left-handed meptazinol prodrug is the compound shown in Formulas I or the stereoisomer of compound, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite or pharmaceutically acceptable salt shown in Formulas I.The liver first-pass effect of the compound is low, bioavilability is high, and the medicine with the compound as active component can be used to treat nerve degenerative diseases or all kinds of Acute or chronic pains, such as wound, postoperative, obstetrics and cancer pain, migraines and neuropathic pain etc..

Description

Left-handed meptazinol prodrug and its production and use

Priority information

The application ask on December 11st, 2015 submitted to China national Department of Intellectual Property, number of patent application be The priority and rights and interests of 201510920412.1 patent application, and by referring to being incorporated by herein.

Technical field

The present invention relates to biomedicine field, in particular it relates to left-handed meptazinol prodrug and preparation method thereof And purposes.

Background technology

Meptazinol (Meptazino1) is an effective antalgesic for Small side effects, and intramolecular has a chiral centre, Hydrochloride with racemic modification in 1986 is listed, and due to curative effect affirmative, obtains market accreditation, is collected for British Pharmacopoeia within 1998. Compared with other opium kind analgesicses, its respiration inhibition and the side effect such as additive are extremely low, therefore do not belong to " anaesthetic " management area.Together When, two optical enantiomorphs of meptazinol are presented different bioactivity, especially to acetylcholinesterase (AChE) On inhibition, levo form activity is far above d-isomer.

It is the effective ways in innovation drug research to generally acknowledging that effective medicine carries out Prodrug formed designs.Pro-drug grinds Study carefully is, with existing medicine as lead compound, structural modification to be carried out to it and optimizes that its medicine is dynamic and pharmacodynamic properties.By this side Method, the absorption that can not only improve medicine, the toxicity for reducing medicine and adverse reaction, and can be effective using existing slow release method Extension drug treating time, strengthens targeting of medicine etc..Usual prodrug compound prepare it is simple and easy to apply, also with small investment, The advantages of risk is small.

At present, meptazinol prodrug needs further exploitation.

The content of the invention

It is contemplated that at least solving one of technical problem in correlation technique to a certain extent.

The present invention is to be based on the following discovery of inventor and complete：

The liver first-pass effect of meptazinol is serious, and phenolic hydroxyl group is rapidly at liver by glucuronidation after oral absorption Or sulphation, so as to form water soluble metabolites and be discharged in urine, bioavilability is not high, only about 8%.

Meanwhile, studies have found that, (-)-meptazinol (left-handed meptazinol) is far longer than to the inhibitory activity of AChE (+)-meptazinol (dextrorotation meptazinol).

Based on above mentioned problem and discovery, inventor has carried out appropriate chemical modification to left-handed meptazinol, makes itself and its Its group is connected through chemical bond, temporary transient chemical combination is formed, so as to change or modify the materialization of left-handed meptazinol Matter, effectively prevents the formation of phenolic hydroxyl group conjugate.In the present invention, inventors herein propose left-handed meptazinol ester prodrug and its Preparation method, left-handed meptazinol ester prodrug molecule in vivo enzymatically or non-enzymatic chemical reaction, be transformed into left-handed U.S. general His phenol and play a role, left-handed meptazinol ester prodrug can effectively mitigate liver first-pass effect, improve left-handed meptazinol Bioavilability.

In the first aspect of the present invention, the present invention proposes a kind of compound.Embodiments in accordance with the present invention, the chemical combination Thing is the compound shown in Formulas I or the stereoisomer of compound, geometric isomer, dynamic isomer, nitrogen oxidation shown in Formulas I Thing, hydrate, solvate, metabolite or pharmaceutically acceptable salt,

Wherein, R is ester group, and compound shown in Formulas I is left-handed meptazinol ester prodrug molecule.Reality of the invention Example is applied, compound proposed by the invention effectively prevents the formation of phenolic hydroxyl group conjugate, is effectively reduced liver first-pass effect, Improve the bioavilability of left-handed meptazinol.

Embodiments in accordance with the present invention, above-claimed cpd can also further have following additional technical feature at least it One：

Embodiments in accordance with the present invention, the ester group includes being selected from bound phosphate groups, carbonate group, amino carbonic ester At least one of group.Embodiments in accordance with the present invention, compound (left-handed U.S. containing above-mentioned ester group proposed by the invention His phenolic ester class prodrugs general) formation of phenolic hydroxyl group conjugate is effectively prevent, liver first-pass effect is effectively reduced, improve The bioavilability of left-handed meptazinol.

In the second aspect of the present invention, the present invention proposes a kind of method for preparing above-claimed cpd.It is of the invention Embodiment, methods described includes：Compound shown in Formula II is carried out into esterification, to obtain compound shown in Formulas I,

Wherein, compound shown in Formula II is left-handed meptazinol.Embodiments in accordance with the present invention, left-handed meptazinol is carried out Esterification, so as to obtain left-handed meptazinol ester prodrug molecule, left-handed meptazinol ester prodrug molecule is effectively reduced Liver first-pass effect, improves the bioavilability of left-handed meptazinol.

Embodiments in accordance with the present invention, the method for above-mentioned prepare compound can also further have following supplementary technology special At least one levy：

Some embodiments of the invention, when the R in compound shown in Formulas I is bound phosphate groups, methods described bag Include：Compound shown in Formula II is contacted with POCl3, triethylamine and ethanol, so as to compound shown in production III,

Wherein, the contact is carried out in dichloromethane, and compound shown in formula III is the left-handed meptazinol of phosphate Prodrugs.POCl3 is that bound phosphate groups introduce compound.Embodiments in accordance with the present invention, by method of the present invention system The left-handed meptazinol prodrug molecule of standby phosphate, shields phenolic hydroxyl group, and low with liver first-pass effect, bioavilability is high Feature.

Some embodiments of the invention, when the R in compound shown in Formulas I is bound phosphate groups, methods described is entered One step includes：To adding POCl3 in the first anhydrous methylene chloride, and 0~5 DEG C is cooled to, to obtain solution A；To second Compound and triethylamine shown in Formula II are added in anhydrous methylene chloride, and is well mixed, to obtain solution B；Solution B is added dropwise To solution A, then reacted 1 hour in 0 DEG C, to obtain solution C；To adding ethanol in solution C, and room temperature is warmed naturally to, Then in being reacted 0.5 hour under stirring, to obtain solution D；Solution D is concentrated successively, is purified, to obtain formula Compound shown in III, wherein, the first anhydrous methylene chloride, POCl3, the second anhydrous methylene chloride, compound shown in Formula II, The usage ratio of triethylamine and ethanol is 3ml:1.1mmol:1ml:0.9mmol:4.3mmol:2ml.Implementation of the invention Bound phosphate groups are introduced left-handed his phenol beautiful by example by the above method, and the left-handed meptazinol prodrug molecule of phosphate for obtaining exists The phosphate that can be widely present in human body is hydrolyzed to rapidly the left-handed meptazinol of active compound and plays a role, so as to reach raising Bioavilability.

In the third aspect of the present invention, the present invention proposes left-handed meptazinol ester prodrug molecule in medicine is prepared Purposes, the medicine is used to treat nerve degenerative diseases or Acute or chronic pain.

Embodiments in accordance with the present invention, the Acute or chronic pain includes wound, postoperative, obstetrics and cancer pain, migraines Or neuropathic pain.

Embodiments in accordance with the present invention, the nerve degenerative diseases include Alzheimer disease and Parkinson's disease.

Embodiments in accordance with the present invention, left-handed meptazinol ester prodrug molecule proposed by the invention is used to prepare medicine Thing, the medicine is used to treat nerve degenerative diseases or a series of pain diseases, including all kinds of Acute or chronic pains, such as creates Wound, postoperative, obstetrics and cancer pain, migraines and neuropathic pain etc. are evident in efficacy.

Additional aspect of the invention and advantage will be set forth in part in the description, and will partly become from the following description Obtain substantially, or recognized by practice of the invention.

Brief description of the drawings

Of the invention above-mentioned and/or additional aspect and advantage will become from description of the accompanying drawings below to embodiment is combined Substantially and be readily appreciated that, wherein：

Fig. 1-Fig. 2 is shown according to one embodiment of the invention, for the pain reaction record of mechanical hyperalgesia test Table；

Fig. 3 is shown according to one embodiment of the invention, under various dose, different time points, the left-handed anti-pain of meptazinol Feel super quick Contrast on effect result.

Specific embodiment

Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining this hair It is bright, and be not considered as limiting the invention.

Compound

Wherein, R is ester group, and compound shown in Formulas I is left-handed meptazinol ester prodrug molecule.Reality of the invention Example is applied, the solubility of compound proposed by the invention does not have marked difference with left-handed meptazinol, and with good change Stability and enzyme metabolic activity are learned, it enzymatically chemically reacts in vivo, can be transformed into left-handed meptazinol and play a role, from And compound proposed by the invention effectively prevents the formation of phenolic hydroxyl group conjugate, liver first-pass effect is effectively reduced, carried The bioavilability of left-handed meptazinol high.

The method of prepare compound

Wherein, compound shown in Formula II is left-handed meptazinol.Embodiments in accordance with the present invention, left-handed meptazinol is carried out Esterification, so as to obtain left-handed meptazinol ester prodrug molecule, left-handed meptazinol ester prodrug molecule possesses preferably Water solubility, chemical stability and enzyme metabolic activity, compared with the left-handed meptazinol of active compound, can effectively shield parent molecule phenol hydroxyl Base, is effectively reduced liver first-pass effect, can effectively improve bioavilability.

Some specific examples of the invention, can by by compound shown in Formula II with selected from POCl3 or its spread out Biology is contacted and is realized esterification.POCl3 or derivatives thereof carries out esterification with left-handed meptazinol, so that Obtain the left-handed meptazinol prodrug molecule of phosphate ester.

Below as a example by preparing the left-handed meptazinol prodrug molecule of phosphate, it is general that detailed description prepares left-handed U.S. of the invention The method of his phenol prodrugs：

Prepare the method (compound shown in formula III) of the left-handed meptazinol prodrug molecule of phosphate

Embodiments in accordance with the present invention, when the R in compound shown in Formulas I is bound phosphate groups, method includes：By Formula II Shown compound is contacted with POCl3, triethylamine and ethanol, so as to compound shown in production III,

Embodiments in accordance with the present invention, when the R in compound shown in Formulas I is bound phosphate groups, method is further included： To adding POCl3 in the first anhydrous methylene chloride, and 0~5 DEG C is cooled to, to obtain solution A；To the second anhydrous dichloro Compound and triethylamine shown in Formula II are added in methane, and is well mixed, to obtain solution B；Solution B is dropped into solution A, Then reacted 1 hour in 0 DEG C, to obtain solution C；To adding ethanol in solution C, and room temperature is warmed naturally to, then in stirring Mix and react 0.5 hour under state, to obtain solution D；Solution D is concentrated successively, is purified, to obtain shown in formula III Compound, wherein, the first anhydrous methylene chloride, POCl3, the second anhydrous methylene chloride, compound, triethylamine shown in Formula II It is 3ml with the usage ratio of ethanol:1.1mmol:1ml:0.9mmol:4.3mmol:2ml.Embodiments in accordance with the present invention, pass through Bound phosphate groups are introduced left-handed his phenol beautiful by the above method, can improve the permeable membrane ability of medicine, increase the stability of medicine, are prolonged Drug treating time long, reduces medical surfaces elimination factor；The left-handed meptazinol prodrug of phosphate point prepared by the above method The phosphate that son can be widely present in human body is hydrolyzed to rapidly the left-handed meptazinol of active compound and plays a role, and can effectively carry High bioavilability.

Purposes of the compound in medicine is prepared

It should be noted that left-handed meptazinol has significant inhibitory activity to acetylcholinesterase, and breathe suppression System and the side effect of additive grade are extremely low, and analgesic effect is notable.Left-handed meptazinol ester prodrug molecule proposed by the invention with Left-handed beautiful his phenol of composing has identical drug effect, but its bioavilability is significantly improved, therefore left-handed U.S. proposed by the invention His phenolic ester class prodrugs general are used to prepare medicine, and the medicine is used to treat nerve degenerative diseases or a series of pain diseases Disease, including all kinds of Acute or chronic pains, such as wound, postoperative, obstetrics and cancer pain, migraines and neuropathic pain etc. are being taken On the premise of same dose, raising evident in efficacy.

In another aspect of this invention, the present invention proposes a kind of for treating nerve degenerative diseases or a series of pains The pharmaceutical composition of pain disease, its include left-handed meptazinol ester prodrug molecule or pharmaceutically acceptable salt as activity into Point.Thus, nerve degenerative diseases or a series of pain diseases can be effectively treated using the pharmaceutical composition, including it is each Class Acute or chronic pain, such as wound, postoperative, obstetrics and cancer pain, migraines and neuropathic pain etc..

Some embodiments of the invention, the drug regimen comprising left-handed meptazinol ester prodrug molecule of the invention Thing can also include pharmaceutically acceptable carrier, and the formulation and administering mode of pharmaceutical composition are not particularly limited.For It is administered orally, the pharmaceutically acceptable carrier can include adhesive, lubricant, disintegrant, excipient, solubilizer, dispersion Agent, stabilizer, suspending agent, colouring agent and aromatic.For ejection preparation, pharmaceutically acceptable carrier can include buffering Agent, preservative, anodyne, solubilizer, isoosmotic pressure agent (isotonic agent) and stabilizer.For the preparation of local administration, Pharmaceutically acceptable carrier can include alkali, excipient, lubricant and preservative.Pharmaceutical composition of the invention can with it is upper The pharmaceutically acceptable carrier stated is combined and is prepared to various formulations.For example, for being administered orally, pharmaceutical composition can be by It is prepared into small pieces, tablet, capsule, elixir, suspension, syrup or thin slice.For ejection preparation, pharmaceutical composition can be produced Into the ampoule or the haplotype formulation of such as multi-dose container of the formulation of such as dose.Pharmaceutical composition can also be produced Into solution, suspension, tablet, pill, capsule and durative action preparation.

Wherein, some specific examples of the invention, be adapted to excipient and dilution in the carrier of pharmaceutical formulation can To include：Lactose, glucose, sucrose, D-sorbite, mannitol, xylitol, erythritol, maltitol, starch is Arabic Rubber, alginates, gel, calcium phosphate, calcium silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, Water, methyl hydroxybenzoate, Nipasol, talcum, magnesium stearate and mineral oil.

Other embodiments of the invention, can also include filler, anticoagulation in pharmaceutical composition of the invention Agent, lubricant, NMF, aromatic and preservative.

Embodiments in accordance with the present invention, left-handed meptazinol ester prodrug molecule of the invention and with left-handed meptazinol ester Class prodrugs are capable of the activity of acetylcholine esterase inhibition, respiration inhibition and additive pair for the pharmaceutical composition of active component Effect is low, thus, medicine with left-handed meptazinol ester prodrug molecule as active component of the invention and left-handed comprising this The pharmaceutical composition of meptazinol ester prodrug molecule can be in treatment nerve degenerative diseases or a series of pain diseases, bag Include all kinds of Acute or chronic pains, such as wound, postoperative, obstetrics and cancer pain, be administered when migraines and neuropathic pain etc..

The term " administration " for being used herein refers to and for the material of scheduled volume to introduce patient by certain suitable mode. Medicine with left-handed meptazinol ester prodrug molecule as active component of the invention can be given by any common approach Medicine, as long as it can reach expected tissue.The various modes of administration can be it is contemplated that including peritonaeum, vein, muscle, skin Under, cortex is orally, local, nasal cavity, lung and rectum, but the invention is not restricted to administering mode that these have been illustrated.However, During due to being administered orally, the active component of the composition of oral administration should be coated or be formulated to prevent it from being dropped in stomach Solution.Additionally, pharmaceutical composition of the invention can use and by active component be sent to the particular instrument of target cell and be administered.

The administration frequency and dosage of pharmaceutical composition of the invention can be determined by multiple correlative factors, the factor bag The disease type to be treated is included, method of administration, patient age, sex, the order of severity and conduct of body weight and disease is active The drug type of composition.Some embodiments of the invention, daily dose can be divided into 1 dose, 2 doses or multi-agent of suitable form, with With 1 time, 2 times or multiple dosing within the whole time period, as long as reaching therapeutically effective amount.

Term " therapeutically effective amount " refers to the amount that compound is enough to significantly improve some symptoms related to disease or illness, Also it is given illness and dosage regimen provides the amount of therapeutic effect.For example, in treatment nerve degenerative diseases or throe, It should be therapeutically effective to reduce, prevent, delay, suppress or block the medicine or compound of any symptom of disease or illness. The medicine or compound of therapeutically effective amount do not need cure diseases or illness, but will be that disease or illness provide treatment so that individual The breaking-out of the disease or illness of body is delayed, prevents or prevents, or the symptom of disease or illness is alleviated, or disease or The time limit of illness is changed, such as disease or illness become not serious, or accelerates rehabilitation.

Term " treatment " is used to refer to the desired pharmacology of acquisition and/or physiologic effect.The effect is just wholly or in part Can be preventative for prevention disease or its symptom, and/or just partially or completely cure diseases and/or disease are caused not Can be curative for good action." treatment " used herein covers mammal, the disease of particularly people and (refers mainly to god Through DD or pain) treatment, including：A but () in easily illness prevents disease in not yet making a definite diagnosis the individuality fallen ill Sick (such as prevention of neurodegenerative diseases) or illness occur；B () suppresses disease, for example, block disease development；Or (c) alleviates disease Disease, for example, mitigate the symptom related to disease." treatment " used herein cover by medicine or compound give individuality to treat, Cure, alleviate, improve, mitigate or suppress any medication of individual disease, will including but not limited to contain as herein described with a left side Rotation meptazinol ester prodrug molecule gives individuality in need for the medicine of active component.

Embodiments in accordance with the present invention, the medicine with left-handed meptazinol ester prodrug molecule as active component of the invention Or pharmaceutical composition can be combined with conventional treatments and/or therapy and use, or can be with conventional treatments and/or therapy It is used separately.When the medicine with left-handed meptazinol ester prodrug molecule as active component of the invention or pharmaceutical composition are being adopted During with being administered in the conjoint therapy with other medicines, they can sequentially or simultaneously give individuality.Or, medicine of the invention Composition can include left-handed meptazinol ester prodrug molecule of the invention, pharmaceutically acceptable carrier or pharmaceutically acceptable Excipient and other curatives known in the art or preventive medicine combination.

The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Unreceipted particular technique or bar in embodiment Part, carried out according to the technology or condition described by document in the art or according to product description.Agents useful for same or instrument The unreceipted production firm person of device, be can by city available from conventional products.

Embodiment 1 prepares the left-handed meptazinol prodrug molecule (compounds X W10091) of phosphate

Wherein, compound shown in formula III is the left-handed meptazinol prodrug molecule of phosphate, also referred to as compound “XW10091”。

(1) to addition 0.2g (1.1mmol) POCl3s (POCl in 3mL anhydrous methylene chlorides (DCM)₃), use ice-water bath It is cooled to 0-5 DEG C；

(2) to addition 0.2g (0.9mmol) left-handed meptazinol solid in 1mL anhydrous methylene chlorides

With 0.4g (4.3mmol) triethylamine, after being well mixed, the dichloromethane of the POCl3 obtained by step (1) is dropped to In alkane solution, 0 DEG C is reacted 1 hour；

(3) to 2mL ethanol (EtOH) is added in step (2) resulting solution, room temperature is warmed naturally to,

Stirring reaction 0.5 hour；

(4) step (3) resulting solution is sequentially passed through into concentration, it is left-handed that neutral preparative separation purifying obtains 160mg phosphates Meptazinol prodrug molecule, yield is 51%.

The left-handed meptazinol prodrug molecule of phosphate¹H NMR and MS (ESI) analyze data is as follows：

¹H NMR(400MHz,DMSO-d₆) δ=7.32 (t, J=7.8Hz, 1H), 7.18-7.14 (m, 2H), 7.00 (d, J =8.0Hz, 1H), 4.17-4.10 (m, 4H), 2.78 (d, J=14.0Hz, 1H), 2.64-2.37 (m, 3H), 2.30 (s, 3H), 2.03-1.98 (m, 1H), 1.75-1.49 (m, 6H), 1.48-1.34 (m, 1H), 1.24 (t, J=7.4Hz, 6H), 0.51 (t, J =7.4Hz, 3H)；MS(ESI):370.2[M+1]⁺。

Embodiment 2 prepares left-handed meptazinol prodrug molecule (compounds X W10093)

To 0.16g (1.0mmol) POCl3 is added in 4mL anhydrous methylene chlorides, 0-5 DEG C is cooled to ice-water bath.To 0.2g (0.86mmol) left-handed meptazinol and triethylamine 0.4g (4.3mmol) are added in 1mL anhydrous methylene chlorides, is well mixed Afterwards, drop in the dichloromethane solution of POCl3,0 DEG C of 1 hour of reaction, add 2mL water to warm naturally to be stirred at room temperature 0.5 hour, concentration prepared purifying and obtains 0.2g pale yellow oils, yield 75%.

¹H NMR(400MHz,D₂O) δ=7.47 (t, J=8.2Hz, 1H), 7.37-7.23 (m, 2H), 7.23-7.10 (m, 1H), 3.85 (d, J=14.4Hz, 1H), 3.61 (d, J=14.4Hz, 1H), 3.23 (t, J=6.0Hz, 2H), 2.89 (s, 3H), 2.49 (dd, J=6.0,14.4Hz, 1H), 2.02-1.83 (m, 3H), 1.82-1.50 (m, 4H), 0.61 (t, J=7.4Hz, 3H)；MS(ESI):314.4[M+1]⁺。

Embodiment 3 prepares left-handed meptazinol prodrug molecule (compounds X W10187)

Compounds X W10187 is left-handed meptazinol prodrug molecule：Left-handed meptazinol ethyl carbonate ester.

0.3g (1.3mmol) left-handed meptazinol and 195.0mg (1.9mmol) triethylamine are dissolved in 6mL dichloromethane, Form homogeneous phase solution.Solution is cooled to 0 DEG C with ice-water bath, 167.0mg (1.5mmol) ethyl chloroformate is added dropwise.Reaction solution is certainly 10mL dchloromethanes are stirred 16 hours and added after being so warming up to 25 DEG C.The reaction solution for diluting successively with 10mL water and 10mL salt is washed.Organic phase is collected, dried, filtered, being concentrated to give grease, silica gel column chromatography (petroleum ether：Ethyl acetate=5/ 1-1/1) 280.0mg grease is obtained.The grease is dissolved in (concentration about 2M) in 2mL hydrochloric ethyl acetate solution, and 25 DEG C are stirred 16 hours, have faint yellow solid to separate out, and filtered, be dried to obtain 150.0mg faint yellow solid compounds, are product Hydrochloride form, yield 34%.

¹H NMR(400MHz,D₂O) δ=7.55 (t, J=8.0Hz, 1H), 7.41 (d, J=7.6Hz, 1H), 7.31 (s, 1H), 7.19 (d, J=8.4Hz, 1H), 4.33 (q, J=7.0Hz, 2H), 3.85 (d, J=14.4Hz, 1H), 3.62 (d, J= 14.0Hz, 1H), 3.22 (t, J=5.8Hz, 2H), 2.86 (s, 3H), 2.45 (dd, J=4.8,14.8Hz, 1H), 2.04-1.49 (m, 7H), 1.34 (t, J=7.2Hz, 3H), 0.57 (t, J=7.2Hz, 3H)；MS(ESI):306.3[M+1]⁺。

Embodiment 4 prepares left-handed meptazinol prodrug molecule (compounds X W10190)

Compounds X W10190 is left-handed meptazinol prodrug molecule：Left-handed meptazinol butylperoxyisopropyl carbonate.

0.2g (0.86mmol) left-handed meptazinol and 95.4mg (0.9mmol) triethylamine are dissolved in 2mL dichloromethane, Form homogeneous phase solution.Solution is cooled to 0 DEG C with ice-water bath, 115.5mg (0.9mmol) isopropyl chlorocarbonate is added dropwise.Reaction solution 10mL dchloromethanes are stirred 16 hours and added after warming naturally to 25 DEG C.The reaction solution for diluting successively with 10mL water and 10mL salt is washed.Organic phase is collected, dried, filtered, being concentrated to give grease, silica gel column chromatography (petroleum ether：Ethyl acetate= 10/1-3/1) 280.0mg grease is obtained.The grease is dissolved in (concentration about 2M) in 2mL hydrochloric ethyl acetates, and 25 DEG C stirring 16 hours, there is solid to separate out, filter, be dried to obtain 150.0mg white solids, be the hydrochloride form of product, yield 57%.

¹H NMR(400MHz,D₂O) δ=7.56 (t, J=8.0Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.31 (s, 1H), 7.19 (d, J=8.0Hz, 1H), 5.02-4.96 (m, 1H), 3.86 (d, J=14.4Hz, 1H), 3.63 (d, J= 14.0Hz, 1H), 3.23 (t, J=5.2Hz, 2H), 2.87 (s, 3H), 2.46 (dd, J=6.0,14.8Hz, 1H), 1.91-1.76 (m, 4H), 1.73-1.49 (m, 3H), 1.36 (d, J=6.0Hz, 6H), 0.59 (t, J=7.2Hz, 3H)；MS(ESI):320.2 [M+1]⁺。

Embodiment 5 prepares left-handed meptazinol prodrug molecule (compounds X W10195)

Compounds X W10195 is left-handed meptazinol prodrug molecule：Left-handed meptazinol cyclohexyl carbonic ester.

Step one：

3.6g (12.0mmol) triphosgene is dissolved in 20mL toluene, forms homogeneous phase solution.The solution is cooled to 0 DEG C, is delayed It is slow that 1.2g (15.0mmol) pyridine is added dropwise, form yellow slurry.After keeping reaction temperature to be stirred 0.5 hour for 0 DEG C, to reaction Middle dropwise addition hexamethylene alcoholic solution (1.0g (10.0mmol) is dissolved in 10mL toluene).After being added dropwise to complete, reaction is changed into white slurry After thing, stirring 1 hour, to adding 30mL water quenchings to go out reaction in reaction, with dichloromethane (2x 30mL) extraction.Collect and combine Machine phase, dries, filters, being concentrated to give 1.1g weak yellow liquids (crude product), yield 69%.Product is chloro-carbonic acid cyclohexyl ester, no Need to purify and be directly used in next step reaction.

Step 2：

0.2g (0.86mmol) left-handed meptazinol and 173.5mg (1.7mmol) triethylamine are dissolved in 2mL dichloromethane In, form homogeneous phase solution.0 DEG C is cooled to ice-water bath, 209.1mg (1.3mmol) chloro-carbonic acid cyclohexyl ester is added dropwise.Reaction solution is certainly 10mL dchloromethanes are stirred 3 hours and added after being so warming up to 25 DEG C.The reaction solution water (2x5mL) for diluting is washed.Receive Collection organic phase, dries, filters, being concentrated to give off-white color grease, silica gel column chromatography (petroleum ether：Ethyl acetate=10/1-3/1) Obtain 240.0mg sticky oil things.The grease is dissolved in 0 DEG C of 2mL hydrochloric ethyl acetates (concentration about 2M), and at 25 DEG C Stirring 16 hours, obtains 200.0mg white solids after concentration, be the hydrochloride form of product, yield 68%.

¹H NMR(400MHz,CDCl₃) δ=7.30 (t, J=8.0Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.12 (s, 1H), 7.01 (dd, J=1.6,8.0Hz, 1H), 4.75-4.67 (m, 1H), 2.84 (d, J=14.0Hz, 1H), 2.58-2.45 (m, 3H), 2.38 (s, 3H), 2.11 (dd, J=8.0,14.4Hz, 1H), 2.02-1.98 (m, 2H), 1.82-1.49 (m, 9H), 1.44-1.22 (m, 6H), 0.59 (t, J=7.4Hz, 3H)；MS(ESI):360.4[M+1]⁺。

Embodiment 6 prepares left-handed meptazinol prodrug molecule (compounds X W10198)

Compounds X W10198 is left-handed meptazinol prodrug molecule：Left-handed meptazinol benzyl carbonic ester.

0.2g (0.86mmol) left-handed meptazinol and 104.1mg (1.0mmol) triethylamine are dissolved in 4mL dichloromethane In, form homogeneous phase solution.0 DEG C is cooled to ice-water bath, 175.5mg (1.0mmol) benzyl chloroformate is added dropwise.Reaction solution rises naturally Stirring is concentrated to give semisolid, silica gel column chromatography (petroleum ether after 3 hours after warm to 25 DEG C：Ethyl acetate=10/1-1/1) obtain 220.0mg pale yellow oils.The grease is dissolved in 2mL hydrochloric ethyl acetates (concentration about 2M), and 16 are stirred at 25 DEG C Hour, blister solid is obtained after concentration, to adding 2mL methyl tertiary butyl ether(MTBE)s to be beaten in the solid 4 hours, form off-white color pulpous state Thing, filtration drying obtains 190.0mg off-white powders, is product hydrochloric acid salt form, yield 55%.

¹H NMR(400MHz,D₂O) δ=7.61-7.45 (m, 6H), 7.42 (d, J=7.2Hz, 1H), 7.29 (s, 1H), 7.19 (d, J=7.6Hz, 1H), 5.34 (s, 2H), 3.84 (d, J=14.0Hz, 1H), 3.62 (d, J=14.0Hz, 1H), 3.22 (t, J=5.6Hz, 2H), 2.86 (s, 3H), 2.45 (d, J=12.8Hz, 1H), 1.92-1.75 (m, 4H), 1.65-1.57 (m, 3H), 0.58 (t, J=7.0Hz, 3H)；MS(ESI):368.8[M+1]⁺。

Embodiment 7 prepares left-handed meptazinol prodrug molecule (compounds X W10199)

Compounds X W10199 is left-handed meptazinol prodrug molecule：Left-handed meptazinol isobutyl group carbonic ester.

0.2g (0.86mmol) left-handed meptazinol and 104.1mg (1.0mmol) triethylamine are dissolved in 4mL dichloromethane In, form homogeneous phase solution.Solution is cooled to 0 DEG C with ice-water bath, 128.8mg (0.9mmol) isobutyl chlorocarbonate is added dropwise.Reaction Liquid is stirred 3 hours after warming naturally to 25 DEG C, adds 10mL dchloromethanes, and the reaction solution for diluting is with water (2x 5mL) Wash, collect organic phase, dry, filter, being concentrated to give off-white color grease, silica gel column chromatography (petroleum ether：Ethyl acetate=10/ 1-1/1) 110.0mg grease is obtained.The grease is dissolved in 2mL hydrochloric ethyl acetates (concentration about 2M), and is stirred at 25 DEG C Mix 16 hours, blister solid is obtained after being concentrated with oil pump, be beaten to addition 1mL methyl tertiary butyl ether(MTBE)s in the solid, filtration drying 70.0mg white solids are obtained, is product hydrochloric acid salt form, yield 22%.

¹H NMR(400MHz,D₂O) δ=7.57 (t, J=7.8Hz, 1H), 7.43 (d, J=6.8Hz, 1H), 7.32 (s, 1H), 7.21 (d, J=8.0Hz, 1H), 4.12 (d, J=6.4Hz, 2H), 3.92-3.80 (m, 1H), 3.64 (d, J=14.0Hz, 1H), 3.24 (br.s., 2H), 2.90 (s, 3H), 2.49 (d, J=12.0Hz, 1H), 2.08-2.01 (m, 1H), 1.98-1.75 (m, 4H), 1.67-1.60 (m, 3H), 0.98 (d, J=6.8Hz, 6H), 0.61 (t, J=7.4Hz, 3H)；MS(ESI):334.3 [M+1]⁺。

Embodiment 8 prepares left-handed meptazinol prodrug molecule (compounds X W10200)

Compounds X W10200 is left-handed meptazinol prodrug molecule：Left-handed meptazinol -4- oxa- THP trtrahydropyranyls Carbonic ester.

Step one：

3.5g (11.8mmol) triphosgene is dissolved in 20mL toluene, forms homogeneous phase solution.The solution is cooled to 0 DEG C, is delayed It is slow that 1.2g (15.0mmol) pyridine is added dropwise, form yellow slurry.After keeping reaction temperature to be stirred 0.5 hour for 0 DEG C, to reaction Middle dropwise addition oxinane -4- alcoholic solutions (1.0g (9.8mmol) is dissolved in 10mL toluene).After being added dropwise to complete, reaction is changed into white After color slurry, stirring 1 hour, to adding 30mL water quenchings to go out reaction in reaction, with ethyl acetate (2x 30mL) extraction.Collect Merge organic phase, dry, filter, being concentrated to give 1.2g colourless liquids (crude product), yield 75%.Product chloro-carbonic acid -4- oxa-s four Hydrogen pyrans ester is not purified, and is directly used in next step reaction.

Step 2：

0.2g (0.86mmol) left-handed meptazinol and 173.5mg (1.7mmol) triethylamine are dissolved in 4mL dichloromethane In, form homogeneous phase solution.Solution is cooled to 0 DEG C with ice-water bath, 211.6mg (1.3mmol) chloro-carbonic acid -4- oxa- tetrahydrochysenes are added dropwise Pyrans ester.Reaction solution is stirred 3 hours after warming naturally to 25 DEG C, adds 10mL dchloromethanes, and the reaction solution for diluting is used Water (2x 5mL) is washed, and collects organic phase, is dried, is filtered, being concentrated to give off-white color grease, silica gel column chromatography (petroleum ether：Acetic acid Ethyl ester=10/1-3/1) obtain 180.0mg pale yellow oils.The grease is dissolved in 0 DEG C of 2mL hydrochloric ethyl acetates (concentration about 2M), and stirred 16 hours at 25 DEG C, blister solid is obtained after being concentrated with oil pump, to addition 2mL methyl in the solid Tertbutyl ether is beaten 4 hours, and filtration drying obtains 180.0mg off-white powders, is product hydrochloric acid salt form, yield 53%.

¹H NMR(400MHz,D₂O) δ=7.56 (t, J=8.0Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 7.32 (s, 1H), 7.21 (d, J=8.0Hz, 1H), 5.03-4.97 (m, 1H), 4.01-3.81 (m, 3H), 3.70-3.58 (m, 3H), 3.27- 3.16(m,2H),2.88(s,3H),2.48-2.41(m,1H),2.15-2.01(m,2H),2.00-1.73(m,6H),1.72- 1.50 (m, 3H), 0.58 (t, J=7.4Hz, 3H)；MS(ESI):362.3[M+1]⁺。

Embodiment 9 prepares left-handed meptazinol prodrug molecule (compounds X W10202)

Compounds X W10202 is left-handed meptazinol prodrug molecule：Left-handed meptazinol-((1R, 2S, 5R) -2- is different Propyl group -5- methyl) cyclohexyl carbonic ester.

Step one：

2.3g (7.7mmol) triphosgene is dissolved in 20mL toluene, forms homogeneous phase solution.The solution is cooled to 0 DEG C, slowly 759.3g (9.6mmol) pyridine is added dropwise, yellow slurry is formed.After keeping reaction temperature to be stirred 0.5 hour for 0 DEG C, to reaction Middle dropwise addition MENTHOL solution (1.0g (6.4mmol) is dissolved in 10mL toluene).After being added dropwise to complete, reaction is changed into white slurry After thing, stirring 1 hour, to adding 30mL water quenchings to go out reaction in reaction, with ethyl acetate (2x 30mL) extraction.Collect and combine Machine phase, dries, filters, being concentrated to give 1.1g colourless liquids (crude product), yield 84%.Crude product chloro-carbonic acid L- menthyl esters are impure Change, be directly used in next step reaction.

Step 2：

0.2g (0.86mmol) left-handed meptazinol and 173.5mg (1.7mmol) triethylamine are dissolved in 4mL dichloromethane In, form homogeneous phase solution.Solution is cooled to 0 DEG C with ice-water bath, 281.2mg (1.3mmol) chloro-carbonic acid L- menthyl esters are added dropwise.Instead Stirred 3 hours after answering liquid to warm naturally to 25 DEG C, add 10mL dchloromethanes, the reaction solution for diluting is with water (2x 5mL) Wash, collect organic phase, dry, filter, being concentrated to give off-white color grease, silica gel column chromatography (petroleum ether：Ethyl acetate=20/ 1-3/1) 190.0mg colorless oils are obtained.The grease is dissolved in 0 DEG C of 2mL hydrochloric ethyl acetates (concentration 2M), and 25 DEG C are stirred 16 hours, and blister solid is obtained after being concentrated with oil pump, and to being added in the solid, the mashing 4 of 2mL methyl tertiary butyl ether(MTBE)s is small When, filtration drying obtains 190.0mg white solids, is product hydrochloric acid salt form, yield 49%.

¹H NMR(400MHz,D₂O) δ=7.54-7.45 (m, 1H), 7.42-7.33 (m, 1H), 7.15-7.02 (m, 2H), 4.65-4.55 (m, 1H), 3.77 (br.s., 1H), 3.57 (d, J=14.0Hz, 1H), 3.34-3.11 (m, 2H), 2.90 (s, 3H), 2.31 (d, J=10.0Hz, 1H), 2.12 (d, J=6.0Hz, 1H), 2.00-1.32 (m, 13H), 1.15-1.01 (m, 2H), 0.88 (t, J=6.2Hz, 6H), 0.78 (d, J=6.4Hz, 3H), 0.54 (t, J=7.0Hz, 3H)；MS(ESI):416.4 [M+1]⁺。

Embodiment 10 prepares left-handed meptazinol prodrug molecule (compounds X W10208)

Compounds X W10208 is left-handed meptazinol prodrug molecule：Left-handed meptazinol (4- methyl) benzyl carbonic acid Ester.

Step one：

2.9g (9.8mmol) triphosgene is dissolved in 20mL toluene, forms homogeneous phase solution.The solution is cooled to 0 DEG C, slowly 971.2g (12.3mmol) pyridine is added dropwise, yellow slurry is formed.After keeping reaction temperature to be stirred 0.5 hour for 0 DEG C, to reaction Middle dropwise addition 4- xylyl alcohols solution (1.0g (6.4mmol) is dissolved in 10mL toluene).After being added dropwise to complete, reaction is changed into stock white After shape thing, stirring 1 hour, to adding 30mL water quenchings to go out reaction in reaction, with ethyl acetate (2x 30mL) extraction.Collect and combine Organic phase, dries, filters, being concentrated to give 1.3g colourless liquids (crude product), yield 87%.Crude product chloro-carbonic acid 4- methyl benzyl ester is not Purifying, is directly used in next step reaction.

Step 2：

0.2g (0.86mmol) left-handed meptazinol and 104.1mg (1.0mmol) triethylamine are dissolved in 4mL dichloromethane In, form homogeneous phase solution.Solution is cooled to 0 DEG C with ice-water bath, 174.1mg (0.9mmol) chloro-carbonic acid 4- methyl benzyl esters are added dropwise. Reaction solution is stirred 3 hours after warming naturally to 25 DEG C, adds 10mL dchloromethanes, the reaction solution for diluting water (2x 5mL) wash, collect organic phase, dry, filter, being concentrated to give off-white color grease, silica gel column chromatography (petroleum ether：Ethyl acetate= 20/1-1/1) 150.0mg pale yellow oils are obtained.The grease is dissolved in into 0 DEG C of 2mL hydrochloric ethyl acetates, and (concentration is about 2M), and at 25 DEG C stir 16 hours, sticky oil thing is obtained after being concentrated with oil pump, to addition 2mL methyl tertbutyls in the solid Ether is beaten 4 hours, and filtration drying obtains 150.0mg white solids, is product hydrochloride form, yield 42%.

¹H NMR(400MHz,D₂O) δ=7.48 (t, J=7.2Hz, 1H), 7.42-7.28 (m, 3H), 7.26-7.01 (m, 4H), 5.21 (s, 2H), 3.73 (br.s., 1H), 3.55 (d, J=14.0Hz, 1H), 3.30-3.10 (m, 2H), 2.84 (s, 3H), 2.41-2.31 (m, 1H), 2.28 (s, 3H), 1.95-1.76 (m, 3H), 1.74-1.43 (m, 4H), 0.51 (t, J= 7.2Hz,3H)；MS(ESI):382.3[M+1]⁺。

Embodiment 11 prepares left-handed meptazinol prodrug molecule (compounds X W10210)

Compounds X W10210 is left-handed meptazinol prodrug molecule：Left-handed meptazinol (N- methyl) -4- piperidyls Base carbonic ester.

127.2mg (0.4mmol) triphosgene is dissolved in 4mL dichloromethane, forms homogeneous phase solution, is cooled to 0 DEG C, is added dropwise The mixing of 148.1mg (1.3mmol) N- methyl piperidine -4- alcohol and 130mg (1.3mmol) triethylamines in 10mL dichloromethane is molten Liquid.Reaction temperature is kept at 0 DEG C, after stirring 0.5 hour, 0.2g (0.8mmol) left-handed Mei Puta is added to disposable in reaction Phenol solid, warm naturally to 25 DEG C stirring 16 hours after.4mL dchloromethanes are added, the reaction solution for diluting is full with 10mL Washed with sodium bicarbonate solution.Organic phase is collected, dried, filtered, being concentrated to give yellow oil, silica gel column chromatography (petroleum ether：Second Acetoacetic ester=10/1-1/1,0.5% triethylamine) obtain pale yellow oil.The grease is dissolved in 0 DEG C of 2mL hydrochloric acid second Acetoacetic ester (concentration about 2M), obtains white slurry thing, and filtration drying obtains 210.0mg white solids, is the hydrochloride shape of product Formula, yield 55%.

¹H NMR(400MHz,D₂O) δ=7.64-7.53 (m, 1H), 7.45 (d, J=7.6Hz, 1H), 7.39-7.31 (m, 1H), 7.27-7.17 (m, 1H), 5.16 (br.s., 1H), 5.06-4.92 (m, 1H), 3.88 (d, J=14.4Hz, 1H), 3.74- 3.58(m,2H),3.53-3.46(m,1H),3.40-3.11(m,4H),3.02-2.86(m,5H),2.61-2.39(m,2H), 2.31 (d, J=15.6Hz, 1H), 2.20-2.11 (m, 1H), 2.10-1.75 (m, 5H), 1.74-1.49 (m, 3H), 0.60 (t, J =7.2Hz, 3H)；MS(ESI):375.0[M+1]⁺。

Embodiment 12 prepares left-handed meptazinol prodrug molecule (compounds X W10212)

Compounds X W10212 is left-handed meptazinol prodrug molecule：Left-handed meptazinol-N- ethoxies acyl group-L- figured silk fabrics Propylhomoserin ester.

Step one：

1.0g (8.5mmol) Valines and 3.1g (22.2mmol) potassium carbonate are dissolved in 10mL water, by solution cooling To after 0 DEG C, 1.2g (11.1mmol) ethyl chloroformate is added dropwise.Reaction be warming up to 25 DEG C stirring 16 hours after, use ethyl acetate (2x 20mL) is washed, and water adjusts pH=2 in ice bath with cold concentrated hydrochloric acid.Ethyl acetate (2x 30mL) is extracted.Collect organic phase, Dry, filter, being concentrated to give 1.5g (60%) N- ethoxies acyl group-Valine, colorless oil.

¹H NMR(400MHz,CDCl₃) δ=5.12 (d, J=9.2Hz, 1H), 4.33 (dd, J=4.6,8.8Hz, 1H), 4.14 (q, J=7.2Hz, 2H), 2.32-2.11 (m, 1H), 1.26 (t, J=7.2Hz, 3H), 1.01 (d, J=6.4Hz, 3H), 0.94 (d, J=7.2Hz, 3H).

Step 2：

0.2g (0.86mmol) left-handed meptazinol and 174.8mg (0.9mmol) N- ethoxies acyl group-Valine are dissolved in In 4mL dichloromethane, to 212.2mg (1.0mmol) DCC and 5mg DMAP are added in the solution, white slurry thing, 25 DEG C are formed Lower stirring is filtered after 16 hours.Reaction solution after filtering adds 10mL dchloromethanes, with saturated ammonium chloride solution (2x 5mL) wash, collect organic phase, dry, filter, being spin-dried for obtaining pale yellow oil, the left-handed U.S.s of 0.2g are obtained after acid preparative separation His phenol-N- ethoxies acyl group-Valine ester hydrochloride, white solid, yield 53% general.

¹H NMR(400MHz,D₂O) δ=7.55 (t, J=7.8Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 7.17-7.06 (m, 2H), 4.33 (d, J=5.2Hz, 1H), 4.12 (q, J=6.8Hz, 2H), 3.84 (d, J=16.0Hz, 1H), 3.61 (d, J =13.6Hz, 1H), 3.21 (t, J=6.0Hz, 2H), 2.85 (s, 3H), 2.50-2.29 (m, 2H), 1.98-1.49 (m, 7H), 1.22 (t, J=7.0Hz, 3H), 1.05 (dd, J=7.0,10.4Hz, 6H), 0.56 (t, J=7.2Hz, 3H)；MS(ESI): 405.2[M+1]⁺。

Embodiment 13 prepares left-handed meptazinol prodrug molecule (compounds X W10216)

Compounds X W10216 is left-handed meptazinol prodrug molecule：Left-handed meptazinol-N- isopropyls oxygen acyl group-L- L-valine ester.

0.2g (0.86mmol) left-handed meptazinol and 191.6mg (0.9mmol) N- isopropyls oxygen acyl group-Valine are dissolved in In 4mL dichloromethane, to 212.2mg (1.0mmol) DCC and 5mg DMAP are added in the solution, white slurry thing, 25 DEG C are formed Lower stirring is filtered after 16 hours.Reaction solution after filtering adds 10mL dchloromethanes, with saturated ammonium chloride solution (2x 5mL) wash, collect organic phase, dry, filter, being spin-dried for obtaining pale yellow oil, the left-handed U.S.s of 0.2g are obtained after acid preparative separation His phenol-N- isopropyls oxygen acyl group-Valine ester hydrochloride, white solid, yield 51% general.

¹H NMR(400MHz,D₂O) δ=7.58 (t, J=8.0Hz, 1H), 7.44 (d, J=7.6Hz, 1H), 7.19-7.09 (m, 2H), 4.94-4.84 (m, 1H), 4.33 (d, J=5.6Hz, 1H), 3.87 (d, J=14.8Hz, 1H), 3.63 (d, J= 14.0Hz,1H),3.32-3.15(m,2H),2.88(s,3H),2.47-2.25(m,2H),2.02-1.55(m,7H),1.37- 1.17 (m, 6H), 1.08 (dd, J=7.0,10.6Hz, 6H), 0.59 (t, J=7.2Hz, 3H)；MS(ESI):419.3[M+1]⁺。

Embodiment 14 prepares left-handed meptazinol prodrug molecule (compounds X W10243)

Compounds X W10243 is left-handed meptazinol prodrug molecule：Left-handed meptazinol -2- acetoxyl group isobutyric acids Ester.

0.3g (1.3mmol) left-handed meptazinol and 156.1mg (1.5mmol) triethylamine are dissolved in shape in 4mL dichloromethane Into homogeneous phase solution, 232.8mg (1.4mmol) 2- acetoxyl group isobutyryl chlorides are added dropwise after reaction solution is cooled into 0 DEG C, stirring 16 is small When after add 10mL dchloromethane reaction solutions, salt solution (2x 8mL) washes.Organic phase is collected, dried, filtered, being concentrated to give half Solid, acidity is prepared and obtains the left-handed meptazinol -2- acetoxyl groups zsobutyrate hydrochlorides of 70mg after purification, colorless oil, Yield 14%.

¹H NMR(400MHz,D₂O) δ=7.56 (d, J=8.0Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.15-7.04 (m, 2H), 3.85 (d, J=14.4Hz, 1H), 3.62 (d, J=14.0Hz, 1H), 3.22 (t, J=5.8Hz, 2H), 2.86 (s, 3H), 2.44 (dd, J=5.6,14.8Hz, 1H), 2.16 (s, 3H), 1.99-1.76 (m, 4H), 1.70 (s, 6H), 1.64-1.54 (m, 3H), 0.57 (t, J=7.4Hz, 3H)；MS(ESI):362.5[M+1]⁺。

Embodiment 15 prepares left-handed meptazinol prodrug molecule (compounds X W10245)

Compounds X W10245 is left-handed meptazinol prodrug molecule：Left-handed meptazinol-N- acetyl group methyl amimoacetic acids Ester.

Step one：

0.2g (0.86mmol) left-handed meptazinol and 178.4mg (0.9mmol) N-Boc- methyl amimoacetic acids are dissolved in 4mL dichloromethanes In alkane, to 212.2mg (1.0mmol) DCC and 5mg DMAP are added in the solution, white slurry thing is formed, 16 are stirred at 25 DEG C Filtered after hour.Reaction solution after filtering adds 10mL dchloromethanes, is washed with saturated ammonium chloride solution (2x 5mL), collects Organic phase, is dried, filters, being spin-dried for obtaining pale yellow oil, and the left-handed meptazinol-N- of 250.0mg are obtained after preparative separation Boc- sarcosinates, pale yellow oil, yield 72%.

¹H NMR(400MHz,CDCl₃) δ=7.38-7.32 (m, 1H), 7.19 (t, J=7.4Hz, 1H), 7.04 (s, 1H), 6.98 (t, J=7.4Hz, 1H), 4.23 (s, 1H), 4.13 (s, 1H), 3.16 (t, J=14.0Hz, 1H), 3.02 (d, J= 11.2Hz, 3H), 2.98-2.79 (m, 2H), 2.59 (d, J=15.2Hz, 3H), 2.72-2.53 (m, 1H), 2.33-2.18 (m, 1H), 1.94-1.66 (m, 6H), 1.64-1.54 (m, 1H), 1.48 (d, J=5.6Hz, 9H), 0.60 (dt, J=2.6,7.0Hz, 3H)。

Step 2：

Left-handed meptazinol-N-Boc- the sarcosinates of 250.0mg (0.6mmol) are dissolved in 4mL dichloromethane, are cooled to 0 DEG C, 1mL trifluoroacetic acids are added, reaction warms naturally to 25 DEG C and stirs 2 hours.Concentrated with oil pump and remove dichloromethane and trifluoro second Acid obtains brown oil, adds 4mL dichloromethane and 187.6mg (1.8mmol) triethylamine, forms brown solution.This is molten Liquid is cold to be gone to 0 DEG C, and 58.2mg (0.7mmol) chloroacetic chloride is added dropwise, and is warming up to 25 DEG C and is reacted 16 hours.Add such as 10mL dichloromethane After dilution, saturated aqueous common salt (2x 5mL) is washed, and collects organic phase, is dried, is filtered, being concentrated to give off-white color grease, acidity system Back-up obtains the left-handed meptazinol-N- acetyl group sarcosinate hydrochlorides of 90mg, faint yellow sticky oil thing, yield after 38%.

¹H NMR(400MHz,CD₃OD) δ=7.53 (t, J=8.0Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.29 (s, 1H), 7.18-7.09 (m, 1H), 4.39 (s, 2H), 3.95 (d, J=14.4Hz, 1H), 3.57 (d, J=14.4Hz, 1H), 3.22 (s,3H),3.27-3.18(m,1H),3.04-2.90(m,3H),2.49-2.36(m,1H),2.23-2.08(m,3H),2.01- 1.56 (m, 7H), 1.31 (t, J=7.2Hz, 1H), 0.63 (t, J=7.2Hz, 3H)；MS(ESI):347.0[M+1]⁺。

Embodiment 16 prepares left-handed meptazinol prodrug molecule (compounds X W10260)

Compounds X W10260 is left-handed meptazinol prodrug molecule：Left-handed meptazinol-N- isobutyryl methyl amimoacetic acids Ester.

Left-handed meptazinol-N-Boc- the sarcosinates of 250.0mg (0.6mmol) are dissolved in 4mL dichloromethane, are cooled to 0 DEG C, 1mL trifluoroacetic acids are added, reaction warms naturally to 25 DEG C and stirs 2 hours.Concentrated with oil pump and remove dichloromethane and trifluoro second Acid obtains brown oil, adds 4mL dichloromethane and 187.6mg (1.9mmol) triethylamine, forms brown solution.This is molten Liquid is cold to be gone to 0 DEG C, and 74.2mg (0.7mmol) isobutyryl chloride is added dropwise, and is warming up to 25 DEG C and is reacted 16 hours.Add 10mL dichloromethane After dilution, salt solution (2x 5mL) is washed, and collects organic phase, is dried, is filtered, being concentrated to give off-white color grease, acid preparative separation After obtain the left-handed meptazinol-N- isobutyryls sarcosinate hydrochlorides of 120.0mg, yield 49%, white blister solid.

¹H NMR(400MHz,CD₃OD) δ=7.57-7.46 (m, 1H), 7.42-7.21 (m, 2H), 7.12 (d, J= 8.0Hz, 1H), 4.36 (s, 2H), 4.02-3.84 (m, 1H), 3.58 (d, J=14.0Hz, 1H), 3.26 (s, 3H), 3.30- 3.17(m,1H),2.93(s,3H),3.16-2.74(m,2H),2.52-2.35(m,1H),2.06-1.52(m,7H),1.13(d, J=6.4Hz, 6H), 0.63 (t, J=7.2Hz, 3H)；MS(ESI):375.2[M+1]⁺。

Embodiment 17 prepares left-handed meptazinol prodrug molecule (compounds X W10258)

Compounds X W10258 is left-handed meptazinol prodrug molecule：Left-handed meptazinol-N- isobutyryls-L- third Propylhomoserin ester.

Step one：

0.2g (0.8mmol) left-handed meptazinol and 178.4mg (0.9mmol) N-Boc-L- alanine are dissolved in 4mL dichloros In methane, to 212.2mg (1.0mmol) DCC and 5mg DMAP are added in the solution, white slurry thing is formed, stirred at 25 DEG C Filtered after 16 hours.Reaction solution after filtering adds 10mL dchloromethanes, is washed with saturated ammonium chloride solution (2x 5mL), receives Collection organic phase, is dried, filters, being spin-dried for obtaining pale yellow oil, and the left-handed Mei Puta of 250.0mg are obtained after neutral preparative separation Phenol-N-Boc-L- alanine esters, yield 72%, pale yellow oil.

¹H NMR(400MHz,CD₃OD) δ=7.54 (t, J=8.0Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.25 (s, 1H), 7.11 (d, J=8.0Hz, 1H), 4.34 (q, J=7.2Hz, 1H), 3.94 (d, J=14.4Hz, 1H), 3.58 (d, J= 14.4Hz, 1H), 3.24 (t, J=6.2Hz, 2H), 2.93 (s, 3H), 2.45-2.40 (m, 1H), 2.08-1.66 (m, 6H), 1.62-1.57 (m, 1H), 1.52 (d, J=7.2Hz, 3H), 1.46 (s, 9H), 0.63 (t, J=7.4Hz, 3H)；MS(ESI): 405.2[M+1]⁺。

Step 2：

Left-handed meptazinol-N-Boc-L- the alanine esters of 250.0mg (0.6mmol) are dissolved in 4mL dichloromethane, are cooled to 0 DEG C, 1mL trifluoroacetic acids are added, reaction warms naturally to 25 DEG C and stirs 2 hours.Concentrated with oil pump and remove dichloromethane and trifluoro Acetic acid obtains brown oil, adds 4mL dichloromethane and 187.6mg (1.9mmol) triethylamine, forms brown solution.Should Solution is cold to be gone to 0 DEG C, and 74.2mg (0.7mmol) isobutyryl chloride is added dropwise, and is warming up to 25 DEG C and is reacted 16 hours.Add such as 10mL dichloros After methane dilution, salt solution (2x 5mL) is washed, and collects organic phase, is dried, is filtered, being concentrated to give off-white color grease, prepared by acidity Left-handed meptazinol-N- isobutyryls-ALANINE the ester hydrochlorides of 120.0mg are obtained after separation, yield 47%, white blister is consolidated Body.

¹H NMR(400MHz,CD₃OD) δ=7.55-7.45 (m, 1H), 7.41-7.31 (m, 1H), 7.23 (s, 1H), 7.09 (d, J=6.4Hz, 1H), 4.51 (q, J=7.2Hz, 1H), 3.95 (d, J=12.0Hz, 1H), 3.57 (d, J=13.6Hz, 1H),3.27-3.17(m,2H),2.93(s,3H),2.58-2.51(m,1H),2.47-2.38(m,1H),2.00-1.60(m, 7H), 1.56 (d, J=7.6Hz, 3H), 1.14 (dd, J=2.8,6.8Hz, 6H), 0.63 (t, J=7.2Hz, 3H)；MS(ESI): 375.1[M+1]⁺。

Embodiment 18 prepares left-handed meptazinol prodrug molecule (compounds X W10271)

Compounds X W10271 is left-handed meptazinol prodrug molecule：(N- (S)-meptazinol oxygen acyl group) ammonia of-L- third Acyl-L-PROLINE.

Step one：

2.0g (9.3mmol) N-Boc-L- proline, 2.0g (18.6mmol) benzylalcohol, 3.6g (18.6mmol) EDCI and 113.5mg (0.9mmol) DMAP is dissolved in 40mL dichloromethane, forms pulpous state liquid.To 4.8g is added dropwise in pulpous state liquid (37.2mmol) N, N- diisopropylethylamine.After being added dropwise to complete, reacted 16 hours at 25 DEG C, add 40mL dchloromethanes, Washed with cold 1M watery hydrochloric acid (2x 80mL), water (100mL) and salt solution (2x 50mL) successively.Organic phase is dried, filtering, is concentrated to give To grease, cross post separation (petrol ether/ethyl acetate=10/1-1/1) and obtain 1.3g N-Boc-L- proline benzyl esters, yield 46%, it is colorless oil.

¹H NMR(400MHz,CDCl₃) δ=7.43-7.28 (m, 5H), 5.31-5.03 (m, 2H), 4.38 (dd, J=3.2, 8.6Hz, 0.4H), 4.26 (dd, J=3.8,8.6Hz, 0.6H), 3.64-3.31 (m, 2H), 2.29-2.11 (m, 1H), 2.05- 1.79(m,3H),1.46(s,3H),1.34(s,6H)。

Step 2：

1.3g (4.3mmol) N-Boc-L- proline benzyl esters are dissolved in 20mL dichloromethane, clear solution are formed, to this 2mL trifluoroacetic acids are added in solution.After being reacted 3 hours at 25 DEG C, concentration removes dichloromethane and trifluoroacetic acid obtains 1.5g L- Proline benzyl ester trifluoroacetate crude product, is pale yellow oil, is directly used in next step reaction.

Step 3：

0.8g (4.2mmol) N-Boc-L- alanine, 1.5g (4.7mmol) L-PROLINE benzyl ester trifluoroacetate crude product and 1.9g (5.1mmol) HATU forms slurry in being dissolved in 40mL dichloromethane, to dropwise addition 1.3g (10.5mmol) in the slurry N, N- diisopropylethylamine.After being added dropwise to complete, reacted 16 hours at 25 DEG C, add 20mL dchloromethanes, successively with cold 1M watery hydrochloric acid (2x 50mL), water (50mL) and salt solution (2x 30mL) are washed.Organic phase is dried, filtering, is concentrated to give grease, mistake Post separation (petrol ether/ethyl acetate=10/1-1/1) obtains 1.3g (82%) N-Boc-L- alanyl-L-proline benzyl esters, nothing Color grease.

¹H NMR(400MHz,CDCl₃) δ=7.43-7.28 (m, 5H), 5.20 (d, J=12.4Hz, 1H), 5.10 (d, J= 12.4Hz,1H),4.65-4.55(m,1H),4.52-4.38(m,1H),3.77-3.65(m,1H),3.65-3.53(m,1H), 2.27-2.15 (m, 1H), 2.06-1.94 (m, 3H), 1.42 (s, 9H), 1.29 (d, J=6.8Hz, 3H).

Step 4：

445.0mg (1.2mmol) N-Boc-L- alanyl-L-proline benzyl esters are dissolved in 4mL dichloromethane, form saturating Bright solution, to addition 1mL trifluoroacetic acids in the solution.After being reacted 3 hours at 25 DEG C, concentration removes dichloromethane and trifluoroacetic acid 0.5g L-Ala-L-Pro benzyl ester trifluoroacetate crude products are obtained, pale yellow oil is directly used in next step reaction.

Step 5：

250.0mg (1.1mmol) left-handed meptazinol is scattered in 4mL dichloromethane, pulpous state liquid is formed, to the pulpous state liquid Middle addition 191.2mg (1.2mmol) CDI.Reaction forms homogeneous settled solution after being heated to reflux 48 hours, is added in reaction Pulpous state liquid is formed after 0.5g (1.2mmol) L-Ala-L-Pro benzyl ester trifluoroacetate crude product, after 25 DEG C are reacted 16 hours 6mL dchloromethanes are added, successively with saturated aqueous common salt (2x 5mL), water (5mL) is washed.Organic phase is collected, is dried, be concentrated to give To semi-solid material, preparative separation obtains 220.0mg (38%) (N- (S)-meptazinol oxygen acyl group)-L- alanyl-L- dried meat ammonia Acid benzyl ester, white solid.

¹H NMR(400MHz,CD₃OD) δ=7.49 (t, J=8.0Hz, 1H), 7.44-7.27 (m, 6H), 7.26-7.16 (m, 1H), 7.14-7.04 (m, 1H), 5.20-5.12 (m, 2H), 4.58-4.40 (m, 2H), 3.92 (d, J=14.4Hz, 1H), 3.83-3.73 (m, 1H), 3.71-3.54 (m, 2H), 3.24 (t, J=6.0Hz, 2H), 2.91 (s, 3H), 2.50-2.39 (m, 1H), 2.30-2.22 (m, 1H), 2.11-1.78 (m, 7H), 1.76-1.50 (m, 3H), 1.35 (d, J=7.2Hz, 3H), 0.62 (t, J=7.4Hz, 3H).

Step 6：

220.0mg (0.4mmol) (N- (S)-meptazinol oxygen acyl group)-L-Ala-L-Pro benzyl ester is dissolved in 4mL first Alcohol, forms homogeneous phase solution, adds 20.0mg palladium carbons, forms black slurry liquid.Filtered after 2 hours in 25 DEG C of hydrogenation reactions, concentration, Neutral preparative separation obtains 90.0mg (N- (S)-meptazinol oxygen acyl group)-L-Ala-L-Pro, and yield 49% is class White powdery solids.

¹H NMR(600MHz,CD₃OD) δ=7.50 (t, J=8.1Hz, 1H), 7.34 (d, J=8.4Hz, 1H), 7.24 (s, 1H), 7.10 (dd, J=1.6,8.1Hz, 1H), 4.51 (q, J=7.2Hz, 1H), 4.46 (dd, J=4.3,8.7Hz, 1H), 3.93 (d, J=13.8Hz, 1H), 3.83-3.75 (m, 1H), 3.72-3.56 (m, 2H), 3.25 (t, J=6.0Hz, 2H), 2.92 (s, 3H), 2.44 (dd, J=6.0,14.4Hz, 1H), 2.30-2.21 (m, 1H), 2.12-1.81 (m, 7H), 1.76-1.67 (m, 1H), 1.67-1.52 (m, 2H), 1.43 (d, J=6.6Hz, 3H), 0.62 (t, J=7.2Hz, 3H)；MS(ESI):446.3[M+ 1]⁺。

Embodiment 19 prepares left-handed meptazinol prodrug molecule (compounds X W10275)

Compounds X W10275 is left-handed meptazinol prodrug molecule：Left-handed meptazinol -1,1 '-dihydroxy isobutyl Acid esters.

Step one：

0.2g (0.8mmol) left-handed meptazinol and 164.8mg (1.0mmol) 5- formyl -2,2- dimethyl -1,3- two The ring of oxygen six is dissolved in 4mL dichloromethane, to 212.2mg (1.0mmol) DCC and 5mg DMAP are added in the solution, forms white Slurry, filters after being stirred 16 hours at 25 DEG C.Reaction solution after filtering adds 10mL dchloromethanes, uses saturated ammonium chloride Solution (2x 5mL) is washed, and collects organic phase, is dried, is filtered, being spin-dried for obtaining pale yellow oil, is obtained after preparative separation 150.0mg (S)-meptazinol -2,2- dimethyl-1,3-dioxane base -5- formic acid esters, yield 47% is white solid.

¹H NMR(400MHz,CDCl₃) δ=7.31 (d, J=8.0,1H), 7.19 (d, J=7.6Hz, 1H), 7.00 (s, 1H), 6.90 (dd, J=1.2,8.0Hz, 1H), 4.26-4.16 (m, 4H), 3.09-3.02 (m, 1H), 2.85 (d, J= 14.0Hz, 1H), 2.60-2.45 (m, 3H), 2.39 (s, 3H), 2.10 (dd, J=8.0,14.4Hz, 1H), 1.77-1.59 (m, 6H), 1.58-1.37 (m, 1H), 1.49 (s, 3H), 1.46 (s, 3H), 0.59 (t, J=7.6Hz, 3H).

Step 2：

Left-handed meptazinol -2,2- dimethyl -1,3- dioxane base -5- the formic acid esters of 30.0mg (0.08mmol) is dissolved in In 1mL acetonitriles and 1mL water, it is 1 to add concentrated hydrochloric acid to adjust pH, and after being reacted 1.5 hours at 25 DEG C, it is 6-7 to add sodium acid carbonate to adjust pH, Concentration removal acetonitrile, preparative separation obtains left-handed meptazinol -1 of 10.0mg under remaining aqueous solution neutrallty condition, and 1 '-dihydroxy is different Butyrate, yield 35% is colorless viscous jelly.

¹H NMR(400MHz,CD₃OD) δ=7.52 (t, J=8.0Hz, 1H), 7.36 (d, J=7.6Hz, 1H), 7.28 (s, 1H), 7.13 (d, J=7.6Hz, 1H), 4.00-3.88 (m, 4H), 3.74-3.45 (m, 2H), 3.25 (t, J=5.8Hz, 2H), 3.07-2.99 (m, 1H), 2.93 (s, 3H), 2.43 (dd, J=6.0,14.4Hz, 1H), 2.06-1.81 (m, 4H), 1.81- 1.70 (m, 1H), 1.69-1.48 (m, 2H), 0.63 (t, J=7.4Hz, 3H)；MS(ESI):336.0.

The prodrugs iii vitro chemical stability test of embodiment 20

1st, chemical stability of the test prodrugs in buffer solution

The buffer solution that pH is respectively 1.2,6.5,7.4 and 8.0 is prepared, it is specific as follows：

The buffer solutions of pH 1.2：765 μ L concentrated hydrochloric acids are taken, 100mL is diluted with water to, obtained final product；The phosphate buffers of pH 6.5：Take phosphorus Acid dihydride potassium 6.8g, plus 1mol/L sodium hydroxide solution 15.2mL, are diluted with water to 1L, obtain final product；The phosphate buffers of pH 7.4： Potassium dihydrogen phosphate 6.8g, plus 1mol/L sodium hydroxide solution 39.5mL are taken, 1L is diluted with water to, obtained final product；The phosphoric acid buffers of pH 8.0 Liquid：Take 2.722g potassium dihydrogen phosphates and be dissolved in water, and be diluted to 100mL, obtain solution A；Take 0.8g NaOH and be dissolved in water, and dilute To 100mL, solution B is obtained；Above 25mL solution As and 23.05mL solution Bs are mixed, and 100mL is diluted to water, obtained final product.

Experiment is implemented as follows：

Buffer solution is preheated 3 minutes in 37 DEG C.The 0.1mg/mL reaction solutions of 0.1mL are added in 1.0mL buffer solutions (respectively For the shown compound that embodiment is prepared).Sample is placed in 37 DEG C of incubations, respectively reaction 0,30 minutes, 1 hour, 2 Hour and 4 hours point sampling analysis, the remaining content of above compound original shape is detected using LC-MS.Take Duplicate Samples Product are analyzed.

The results are shown in Table 1.Knowable to result as shown in Table 1, buffer solution of the shown compound in pH 1.2,6.5,7.4 and 8.0 Middle hatching is presented preferable stability in 2-4 hours.

2nd, stability of the test prodrugs in simulated gastric fluid

Simulated gastric fluid is configured：0.04g sodium chloride and 0.06g pepsins are dissolved in 0.14mL concentrated hydrochloric acids, are added water dilute Release to 20mL.PH value is determined as 1.20 ± 0.05.

Experiment is implemented as follows：From 200 μM of working solutions (storing solution with DMSO dissolve configure, after it is dilute with 50% acetonitrile/water Release) in draw 4 μ L be added in 96 deep-well plates, each time point (T0,1 hour, 2 hours, 3 hours, 24 hours) does one block of plate, often It is secondary to do two parallel (multiple holes).Except T0 points, after 4 μ L test medicine working solutions are added in the deep-well plates of other time point, add The μ L of simulated gastric fluid 396, obtain final concentration of 2 μM of incubation concentration, and organic phase D MSO and acetonitrile concentration for 0.2% with 0.45%.With 300 revs/min of samples of incubation to corresponding time in 37 DEG C of incubators.Test medicine is in corresponding incubation Between after (T0,1 hour, 2 hours, 3 hours, 24 hours) terminate, add contain 200ng/mL tolbutamides and labetalol immediately The μ L of ice acetonitrile 800 of (internal standard) are well mixed.100 μ L liquid are taken out in each hole more than to be added in 96 deep-well plates, is added again The μ L of acetonitrile 200 containing 200ng/mL tolbutamides and labetalol (internal standard) are well mixed.

T0 points prepare：After 4 μ L test medicine working solutions are added in deep-well plates, first add containing 200ng/mL tolbutamides and The μ L terminating reactions of acetonitrile 800 of labetalol (internal standard), add the μ L of simulated gastric fluid 396 it is well mixed after, be taken out 100 μ L Liquid adds the μ L of acetonitrile 200 containing 200ng/mL tolbutamides and labetalol (internal standard) to be well mixed.

96 deep-well plates are placed in 4 DEG C of centrifuges, are centrifuged 20 minutes with 4000 revs/min of rotating speed.Supernatant is taken after centrifugation After the μ L of liquid 60 add 180 μ L water well mixed, sample analysis is carried out with LC/MS/MS.

The results are shown in Table 1.From the above results, shown compound is hatched 24 hours in simulated gastric fluid, is presented preferable Stability.

Table 1 shows that left-handed meptazinol prodrug molecule prepared by previous embodiment is stable in buffer solution, simulated gastric fluid The partial results of property.

Table 1

The metabolic stability measure of the test-compound of embodiment 21

1. rat/people's liver S9 component metabolic stability measures

Determine prepared by previous embodiment using rat/people's liver S9 component metabolic stability measure schemes of the invention Left-handed meptazinol prodrug molecule revolves the release efficiency of meptazinol conversion to the left from prodrug in vitro.

Experiment is implemented as follows：

500 μM of analysis liquid of 40 μ L are added (to be prepared for embodiment respectively in the Tris buffer solutions (pH 7.4) of 360 μ L The compound of acquisition), make its final concentration of 50 μM.The above-mentioned reaction solution several pieces of 20 μ L are taken respectively, are charged with the S9 of 100 μ L Solution (protein content 1mg/mL), 37 DEG C of water-baths preheat 10min, are subsequently adding 80 μ L 1.3mM NADP and start reaction.In 0,5, 10th, 20,30,60min time points ice acetonitrile stop bath (the containing the internal standard thing toluene sulphur fourth of 600 μ L is separately added into toward every part of sample Urea, labetalol, Propranolol and each 200ng/mL of choline) and mesoscale eddies mixing terminating reaction, 4 DEG C, 4000 revs/min of centrifugations 20 minutes, take supernatant sample introduction.Parallel two parts of each sample, the residue using LC-MS/MS methods detection above compound original shape contains The generation content of amount and female medicine.

Result shows (be shown in Table 2)：The external left-handed meptazinol carried out using rat/people's liver S9 components is discharged efficiency and surveyed Surely show that prodrug compound can effectively be metabolized.Wherein rat S9 mother's medicine production rates are relatively low, can quilt with left-handed meptazinol itself Rat S9 continues to be metabolized correlation.In people's liver S9 component metabolisms, prodrug is by rapid metabolization and effectively to discharge left-handed U.S. general His phenol.

2. rat/people's whole blood metabolic stability test

Determine the application compound in vitro from prodrug to female medicine using rat/people's whole blood metabolic stability measure scheme The release efficiency of conversion.

Experiment is implemented as follows：

The test-compound working solution of 250 μM of 2 μ L is mixed in 98 μ L whole bloods so that its final concentration of 5 μM.At 37 DEG C In about 60 revs/min of lower incubation reaction samples in water-bath.It is each from response sample to take out 100 at 0,10,30,60 and 120 minutes μ L, by adding 100 μ L ultra-pure waters and 600 μ L ice acetonitriles, (200ng/mL of thing containing internal reference orinases, 20ng/mL draw shellfish Luo Er) terminating reaction.All samples are vortexed 10 minutes, then 10 minutes is centrifuged with protein precipitation in 4000rpm.By 100 μ L Supernatant is transferred in new plate.Supernatant is diluted using 200 μ L ultra-pure waters, is then shaken up 10 minutes at 800 revs/min.Use LC/MS/MS is analyzed to detect test-compound surplus and left-handed meptazinol formation efficiency to sample.

Result shows (be shown in Table 2)：The external left-handed meptazinol carried out using rat/people's whole blood is discharged potency assay and shown Prodrug compound can change into female medicine with various release efficiencies, and this shows that after prodrug compound is applied to rat/people it can Left-handed meptazinol is converted in system circulation.

Wherein, the vitro enzyme metabolic stability of part of compounds the results are shown in Table 2：

Table 2

Embodiment 22 evaluates left-handed meptazinol to Spinal nerve ligation (Spinal Nerve Ligation, SNL) SD rats The drug action of model

SNL models are directed to the conventional animal model of neuropathic pain assessment.The purpose of this experiment is that the left-handed U.S. of assessment is general He mitigates the super quick effectiveness of SNL rat mechanical hyperalgesias by phenol.

Experimental group：

Test procedure：

SNL models are set up：

1) each group medicine is configured using physiological saline according to different dosing demand as solvent correspondence.

2) operation consent, related to vessel are carried out disinfection aseptic process.

3) all animals are anaesthetized with amobarbital (50mg/kg, intraperitoneal injection).Before operative incision, animal is extruded Toe is confirming holonarcosis before animal surgery.Smear ophthalmic ointment to prevent animal corneal from drying in animal eye.

4) animal lower part of the body operative region hair is shaved off, using Iodophor and 70% ethanol to operation area skin sterilization three Time.After start after dry skin operation.

5) longitudinal cut is opened at animal waist sacrum rear portion using scalpel, exposure left side paraspinal muscle uses dilator Separating muscle tissue is exposing vertebrae.

6) left side L5 and L6 spinal nerves are separated, is closely ligatured with 6-0 silk threads.Wound is closed, while entering to skin Row stitching processing.

7) be placed on animal on electric blanket by Post operation, and hypodermic injection 5mL physiological saline is in case anti-avulsion water.It is complete Deng animal (can be freely movable) puts back in cage animal after revival.

1st, the super quick test of mechanical hyperalgesia

1) rat is separately positioned in lucite box, cartridge bottom can be tested for grid with ensureing rat foot. Rat will adapt to 15 minutes before testing.

2) after the completion of adapting to, tested in the middle part of the rat rear foot using test fiber.Test fiber includes 8 test intensity： 3.61 (0.4g), 3.84 (0.6g), 4.08 (1g), 4.31 (2g), 4.56 (4g), 4.74 (6g), 4.93 (8g), 5.18 (15g). During test, test fiber is vertically pressed into skin and force makes fiber bending 6-8 seconds, each test interval 5 seconds.During test, move Contracting pin is designated as pain reaction to thing rapidly.Animal contracting pin is also designated as pain reaction when test fiber leaves animal skin.If Animal is moved or walks about, and does not remember pain reaction, answers retest.

3) first by 4.31 (2g) when testing, if animal has pain reaction, test next time uses the small one-level of dynamics Test fiber；If animal does not have pain reaction, test next time uses test fiber (the Chaplan et of great efforts one-level al.,J Neurosci Methods 53:55-63,1994).The maximum dynamics for testing fiber is 5.18 (15g).

Test result is recorded in the form shown in Fig. 1-2, has pain reaction to record x, does not have pain reaction to record o.Its In, as shown in Figure 1-2, show the super quick threshold value of mechanical hyperalgesia<4g, does not show the super quick=15g of mechanical hyperalgesia.

Wherein, mechanical hyperalgesia is calculated using equation below：

50% threshold of reaction (g)=(10^(Xf+kδ))/10,000,

Wherein, the final test fiber values for being used in Xf=tests, k=tabular values, δ=mean difference.

2nd, animal and the super quick baseline test of mechanical hyperalgesia are adapted to

Be placed on animal in experimental situation after 10 days adapt to 15 minutes by operation, is continuously adapted to three days in test environment.Give Medicine the previous day (after operation 13 days), the super quick baseline test of mechanical hyperalgesia is carried out, will not show the super quick animal of mechanical hyperalgesia The animal of (contracting pin threshold value is more than 5) is grouped at random after rejecting.

Administration：According to the time administration of EE.

According to data analysis, the SNL model test conclusions are as follows：5 mg/kgs, 10 mg/kgs and 20 milligrams/ Under kilogram various dose, after left-handed meptazinol was administered at 0.5 hour and 1 hour, mechanical hyperalgesia surpasses caused by all realizing SNL Quick reversion.

Under various dose, different time points, the left-handed anti-allodynia Contrast on effect result of meptazinol is shown in Fig. 3.

As shown in figure 3, * p<0.05, * * * p<0.001 is that compound compares with solvent group；#p<0.05, ##p<0.01 being Compound compares with left-handed meptazinol (5mg/kg 0.5h)；^p<0.05, ^^p<0.01 is compound and left-handed meptazinol (5mg/kg 1h) compares, and uses the additional Dunnett multiple comparative tests of one-way analysis of variance；% shows every group of machinery The inhibiting rate of allodynia.

Wherein, the super quick inhibiting rate of mechanical hyperalgesia=(value of the average value-administration group of solvent group)/(solvent group group it is flat Average -15) * 100%.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means to combine specific features, structure, material or spy that the embodiment or example are described Point is contained at least one embodiment of the invention or example.In this manual, to the schematic representation of above-mentioned term not Necessarily refer to identical embodiment or example.And, the specific features of description, structure, material or feature can be any One or more embodiments or example in combine in an appropriate manner.

Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that：Not Can these embodiments be carried out with various changes, modification, replacement and modification in the case of departing from principle of the invention and objective, this The scope of invention is limited by claim and its equivalent.

Claims

1. a kind of compound, it is characterised in that stereoisomer, the geometry of compound shown in the compound or Formulas I shown in Formulas I Isomers, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite or pharmaceutically acceptable salt,

Wherein, R is ester group.

2. compound according to claim 1, it is characterised in that the ester group includes being selected from bound phosphate groups, carbonic acid At least one of ester group, amino carbonate group.

3. a kind of method for preparing the compound described in any one of claim 1~2, it is characterised in that including：

Compound shown in Formula II is carried out into esterification, to obtain compound shown in Formulas I,

4. method according to claim 3, it is characterised in that when the R in compound shown in Formulas I is bound phosphate groups, Methods described includes：

Compound shown in Formula II is contacted with POCl3, triethylamine and ethanol, so as to compound shown in production III,

Wherein, the contact is carried out in dichloromethane.

5. method according to claim 4, it is characterised in that methods described is further included：

To adding POCl3 in the first anhydrous methylene chloride, and 0~5 DEG C is cooled to, to obtain solution A；

To compound and triethylamine shown in addition Formula II in the second anhydrous methylene chloride, and it is well mixed, to obtain solution B；

Solution B is dropped into solution A, is then reacted 1 hour in 0 DEG C, to obtain solution C；

To adding ethanol in solution C, and room temperature is warmed naturally to, it is molten to obtain then in being reacted 0.5 hour under stirring Liquid D；

Solution D is concentrated successively, is purified, to obtain compound shown in formula III,

Wherein, the first anhydrous methylene chloride, POCl3, the second anhydrous methylene chloride, compound, triethylamine and second shown in Formula II The usage ratio of alcohol is 3ml:1.1mmol:1ml:0.9mmol:4.3mmol:2ml.

6. purposes of the compound any one of claim 1~2 in medicine is prepared, the medicine is used to treat nerve DD or Acute or chronic pain.

7. purposes according to claim 6, it is characterised in that the Acute or chronic pain includes wound, postoperative, obstetrics and cancer Disease pain, migraines or neuropathic pain.

8. purposes according to claim 6, it is characterised in that the nerve degenerative diseases include Alzheimer disease and Parkinson's disease.