CN104473927A - Polyethylene glycol and medicine molecule conjugate and preparation method thereof - Google Patents
Polyethylene glycol and medicine molecule conjugate and preparation method thereof Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
The invention provides a polyethylene glycol and medicine molecule conjugate and a preparation method thereof, and an application of the conjugate in preparation of polyethylene glycol bi-nalo alcohol. The preparation method comprises the following steps: preparing a compound in formula I by taking HO-CH2-(CH2OCH2)n-CH2-OH as a reactant; (2) carrying out nucleophilic substitution on medicine molecules or medicine molecules modified by protecting groups and the compound as shown in formula I under an alkaline condition to obtain the compound as shown in formula II, wherein n is an integer from 0-20, L is a leaving group and selected from a group consisting of -OTs, -OMs, -OBs, -OTf, -F, -I, -Br and -Cl; and X1 is first medicine molecules or medicine molecule groups modified by the protecting groups. The method has the advantages that side reaction can be reduced, the total yield of the polyethylene glycol-medicine molecule conjugate is improved and the reaction conditions are easy to control, and thus industrial applicability is excellent.
Description
Technical field
The present invention relates to Polyethylene Glycol and drug molecule conjugate and preparation method thereof, particularly relate to Polyethylene Glycol and naloxol active combination and preparation method thereof, and it is preparing the application in the two naloxol of Polyethylene Glycol.
Background technology
Polyethylene Glycol (PEG) modification technique is the Novel medicine feeding technology developed rapidly in recent years, is mainly used in injection delivery systems.It is a kind of will Polyethylene Glycol activate after be linked to the technology on drug molecule or surface.Medicine small molecule, after polyethyleneglycol modified, has the advantage such as water solublity increase, toxicity reduction of medicine.But, when preparing the conjugate of Polyethylene Glycol and drug molecule at present, often there is productive rate too low, the problem of later separation difficulty, cause preparation cost higher.
Naloxone is that pure opiate receptor picks up drug resistance, and itself is without intrinsic activity, but competitiveness can pick up anti-each opioid receptor, has very strong affinity to μ receptor.Naloxone comes into force rapidly, and it is strong to pick up anti-effect, easily through blood brain barrier, removes central inhibitory action, recovers rapidly the normal function of the internal organs such as brain, the heart, lung, and does not produce the dependency of morphine-like substance, withdrawal symptom and respiration inhibition effect.
Oral naloxone can prevent small intestinal receptor, thus alleviate the constipation side effect that opium causes, but non-patent literature Oralnaloxone reverses opioid-associated constipation (Meissner W et al, Pain, 2000,84 (1): 105-109) report due to significant first-pass effect after oral naloxone, bioavailability is low.Can significantly improve its bioavailability by pegylation naloxone drug molecule, the Pegylation naloxone product NKTR-118 of Nektar Therapeutics's research enters the clinical research of three phases in March, 2011.
The compound of each Polyethylene Glycol in conjunction with a naloxone molecule is disclosed in WO2005058367A1, its preparation process comprises in dimethyl formamide (DMF) solution NaH being added to MEM-naloxone (C1 or C2 structural compounds), at room temperature N
2stir 15 minutes in atmosphere, then add the Polyethylene Glycol DMF solution of end group halogen substiuted, at N
2lower oil bath heating, obtains α and the β stereoisomer mixture of PEG-MEM-naloxone.But said method productive rate is not high, and only can prepare the compound of each Polyethylene Glycol in conjunction with a naloxone molecule, the conjugate molecule of more high drug load cannot be obtained.
Disclose the derivant that each polyethylene glycol structures is connected with two or more naloxol in CN103289075A, its preparation method comprises 2 MEM-naloxols (C1 or C2 structural compounds) are direct and Ms-(OCH
2cH
2)
f-OMs connects acquisition Compound D α or D β under NaH alkali condition.But in said method, prepare yield and be only about 20% in MEM-naloxol, thus cause expensive naloxone hydrochloride utilization rate too low, and follow-up column separating purification is very difficult.
For overcoming the defect of prior art, the invention provides a kind of Polyethylene Glycol-drug molecule conjugate and adopting the method for fractional steps to prepare the method for Polyethylene Glycol-drug molecule conjugate.
Summary of the invention
An object of the present invention is to provide a kind of method preparing Polyethylene Glycol-drug molecule conjugate, solve Polyethylene Glycol and drug molecule association reaction productive rate too low, the problem of later separation difficulty.
Another object of the present invention is to provide a kind of reactive compound of Polyethylene Glycol-drug molecule, can be further used for preparing Polyethylene Glycol-drug molecule conjugate.
Of the present invention also have object to be prepare productive rate by what improve Polyethylene Glycol-many naloxones conjugate, reaches the object of the preparation cost of reduction Polyethylene Glycol-many naloxones conjugate.
Therefore, an aspect of of the present present invention provides the preparation method of a kind of Polyethylene Glycol-drug molecule conjugate, comprising:
(1) with HO-CH
2-(CH
2oCH
2)
n-CH
2-OH is the compound that reactant prepares formula I
(2) by drug molecule or through blocking group modify drug molecule and formula I shown in compound in the basic conditions nucleo philic substitution reaction obtain the compound of general formula I I
Wherein, n is the integer of 0-20;
Described L is leaving group, be selected from by
(-OTs),
(-OMs),
(-OBs),
the group of (-OTf) ,-F ,-I ,-Br and-Cl composition;
Described X
1the drug molecule group being the first drug molecule or modifying through blocking group.
In an embodiment of the invention, described n is preferably the integer of 1-15; More preferably, n is the integer of 2-10; More preferably, n is the integer of 4-9.
In an embodiment of the invention, preferably, described L is
the group of-Br and-Cl composition.More preferred, described L is
In an embodiment of the invention, described drug molecule or the drug molecule being preferably the drug molecule containing-OH through the drug molecule that blocking group is modified or modifying through blocking group.Hydroxyl in drug molecule can be connected with the compound of formula II by nucleophilic substitution.
In the specific embodiment of the present invention, described drug molecule can be respiratory drugs, spasmolytic, muscle-relaxant drug, antibiotic medicine, appetite suppressant, control migrainous medicament, muscle contraction medicine, anti-infective, antiarthritic, antimalarial, antiemetic, trachea expanding agent, antithrombotic, antihypertensive, cardiovascular drug, anti-arrhythmic, antioxidant, antasthmatic, diuretic, lipid modulating agent, antiandrogen, antiparasitic, anticoagulant, antineoplastic agent, hypoglycemia medicine, nutrition medicament, growth enriching substance, anti-enteritis medicament, vaccine, antibody, diagnostic agent and contrast medium.Preferably, described drug molecule is selected from opiates and picks up anti-agent, oxymorphone, codeine, OxyContin, morphine, ethylmorphine hydrochloride, diacetylmorphine, hydromorphone, paracodin, paramorphane and methyldihydromorphine.Described opiates is picked up anti-agent and is selected from naloxone, N-methylnaloxone, 6-amino-14-hydroxyl-17-allyl Jino desomorphine, receive bent grace diindyl, Naltrexone, MNTX, Naboo is fragrant, butorphanol, Cyc, pentazocine, nalorphine, receive bent grace diindyl, Naltrindole, promise third Na Tuofeimin, oxilorphan, 6-amino-6-deoxidation-naloxone, pentazocine, levallorphan methyl naltrexone, buprenorphine, plug clo is all, levallorphan and nalorphine etc.Preferably, described drug molecule is selected from naloxone, N-methylnaloxone, 6-amino-6-deoxidation-naloxone.More preferred, described drug molecule is selected from naloxone.
In an embodiment of the invention; the described drug molecule through blocking group modification refers to that in drug molecule, substituted radical modified through blocking group; preferably, the described drug molecule modified through blocking group refers to that the protected group of hydroxyl in drug molecule modified.Described blocking group is selected from the tert-butyl group, trityl group, TMS, triethyl silyl, Phenylmethoxy, methyl methoxy base, chloromethyl methoxyl group, methoxvethoxvmethvl (MEM-).Preferred, blocking group of the present invention refers to methoxvethoxvmethvl (MEM-), for the hydroxyl in modified medicaments molecule, makes the reaction of the hydroxyl generation step (2) of specific site in drug molecule.
In a specific embodiment of the present invention, described drug molecule or the drug molecule through blocking group modification are the compound with formula C1 or C2.
In an embodiment of the invention, the mode that described step (1) can adopt this area to be suitable for prepares the compound of formula I, such as by method described in patent CN103289075A description embodiment 1, or obtained by the method in patent WO2005058367A1.In a detailed description of the invention, described step (1) is by HO-CH
2-(CH
2oCH
2)
n-CH
2-OH and paratoluensulfonyl chloride, methylsufonyl chloride, p-bromobenzenesulfonyl chloride or trifluoromethanesulfchloride chloride react the compound preparing formula I.
In an embodiment of the invention, described step (2) is reacted in polar non-solute, and reaction temperature is-20 DEG C ~ 100 DEG C.Preferably, the reaction dissolvent of described reaction is selected from by N, the group of dinethylformamide (DMF), N, N-diethylformamide (DMAc), dimethyl sulfoxine (DMSO), hexamethyl phosphoramide (HMP), N-Methyl pyrrolidone (NMP), oxolane, acetone, dioxane, acetonitrile, dichloromethane, chloroform composition.More preferably, the reaction dissolvent of described reaction is selected from the group be made up of DMF, N, N-diethylformamide, dimethyl sulfoxine, oxolane.Particularly preferably, the reaction dissolvent of described reaction is selected from DMF or N, N-diethylformamide.The reaction temperature of described reaction is preferably-20 DEG C ~ 80 DEG C; More preferably, the reaction temperature of described reaction is 0 DEG C ~ 50 DEG C; More preferably, the reaction temperature of described reaction is room temperature.
In an embodiment of the invention, to react addition be 1: 1-4 in molar ratio for described step (2) Chinese medicine molecule or the drug molecule modified through blocking group and formula I.Because step (2) Chinese medicine molecule or two leaving groups in the drug molecule and formula I of blocking group modification all nucleophilic substitution may occur, when drug molecule or excessively add in reaction system through the drug molecule that blocking group is modified, then single step reaction may be there is, namely two leaving groups in formula II compound all replace by drug molecule or through the drug molecule that blocking group is modified, reaction yield can reduce, therefore step (2) Chinese medicine molecule or through blocking group modify drug molecule and Compounds of formula II addition should ensure that formula I is in the excessive state added.Preferably; described step (2) Chinese medicine molecule or be 1: 1-3 in molar ratio through drug molecule and formula I addition that blocking group is modified, the drug molecule described in more preferred or be 1: 1-2 in molar ratio through the drug molecule of blocking group modification and formula II compound addition.
In an embodiment of the invention, described step (2) neutral and alkali condition is under NaH alkali condition.The addition drug molecule of described NaH or the drug molecule modified through blocking group are 1: 1-5 with NaH in molar ratio, are preferably 1: 2-4, more preferably 1: 2-3.
Optional, also include step (3) in the preparation method of a kind of Polyethylene Glycol-drug molecule conjugate of the present invention, slough the step of the protecting group in the compound of general formula I I in the drug molecule group of blocking group modification.Preferably, described step (3) is dissolved by Compounds of formula II, passes into hydrogen chloride gas precursor reactant, after reaction, adds wet chemical and regulates pH to be 7-10, be separated to obtain product
In a specific embodiment of the present invention, the preparation method of described Polyethylene Glycol-drug molecule conjugate, comprising: (1) is by HO-CH
2-(CH
2oCH
2)
n-CH
2-OH dissolves, and adds toluene sulfochloride, cooling, adds KOH and reacts 1-8 hour, be separated the compound obtaining formula I
(2) be dissolved in DMAc by the compound of general formula C1 or C2, cooling, adds NaH in batches, then adds the DMAc solution of compound of formula I, room temperature reaction, is separated the compound obtaining general formula I I after reaction
the addition of the compound of its formula of C1 or C2 and the compound of formula I is 1: 1-2 in molar ratio.
Another aspect of the present invention additionally provides the preparation method of a kind of Polyethylene Glycol-drug molecular bond, comprising:
(1) with HO-CH
2-(CH
2oCH
2)
n-CH
2-OH is the compound that reactant prepares formula I
(2) by the first drug molecule or through blocking group modify drug molecule and formula I shown in compound in the basic conditions nucleo philic substitution reaction obtain the compound of general formula I I
(3) by the second drug molecule or through blocking group modify drug molecule and general formula I I compound in the basic conditions nucleo philic substitution reaction obtain the compound of general formula III
Wherein, n is the integer of 0-20;
Described L is leaving group, be selected from by
the group of-F ,-I ,-Br and-Cl composition;
Described X
1the the first drug molecule group being the first drug molecule or modifying through blocking group; X
2the the second drug molecule group being the second drug molecule or modifying through blocking group.
In an embodiment of the invention, the first described drug molecule or the drug molecule through blocking group modification can be identical with the second drug molecule or the drug molecule through blocking group modification, also can be different.In an embodiment of the invention, the first drug molecule or through blocking group modify drug molecule group and the second drug molecule or through blocking group modify drug molecule group be preferably containing-OH drug molecule or through blocking group modify drug molecule.
In the specific embodiment of the present invention, first drug molecule or through blocking group modify drug molecule and the second drug molecule or through blocking group modify drug molecule independently selected from respiratory drugs, spasmolytic, muscle-relaxant drug, antibiotic medicine, appetite suppressant, control migrainous medicament, muscle contraction medicine, anti-infective, antiarthritic, antimalarial, antiemetic, trachea expanding agent, antithrombotic, antihypertensive, cardiovascular drug, anti-arrhythmic, antioxidant, antasthmatic, diuretic, lipid modulating agent, antiandrogen, antiparasitic, anticoagulant, antineoplastic agent, hypoglycemia medicine, nutrition medicament, growth enriching substance, anti-enteritis medicament, vaccine, antibody, diagnostic agent and contrast medium.Preferably, the first described drug molecule or through blocking group modify drug molecule and the second drug molecule or through blocking group modify drug molecule pick up anti-agent, oxymorphone, codeine, OxyContin, morphine, ethylmorphine hydrochloride, diacetylmorphine, hydromorphone, paracodin, paramorphane and methyldihydromorphine independently selected from opiates.Described opiates is picked up anti-agent and is selected from naloxone, N-methylnaloxone, 6-amino-14-hydroxyl-17-allyl Jino desomorphine, receive bent grace diindyl, Naltrexone, MNTX, Naboo is fragrant, butorphanol, Cyc, pentazocine, nalorphine, receive bent grace diindyl, Naltrindole, promise third Na Tuofeimin, oxilorphan, 6-amino-6-deoxidation-naloxone, pentazocine, levallorphan methyl naltrexone, buprenorphine, plug clo is all, levallorphan and nalorphine etc.Preferably, the first described drug molecule or through blocking group modify drug molecule and the second drug molecule or through blocking group modify drug molecule be selected from naloxone, N-methylnaloxone, 6-amino-6-deoxidation-naloxone.In a specific embodiment of the present invention, the first described drug molecule or through blocking group modify drug molecule group and the second drug molecule or through blocking group modify drug molecule independently selected from the compound with formula C1 or C2.
In an embodiment of the invention, described step (3) is reacted in polar non-solute, and reaction temperature is-20 DEG C ~ 100 DEG C.Preferably, the reaction dissolvent of described reaction is selected from by N, the group of dinethylformamide, N, N-diethylformamide, dimethyl sulfoxine, hexamethyl phosphoramide, N-Methyl pyrrolidone, oxolane, acetone, dioxane, acetonitrile, dichloromethane, chloroform composition.More preferably, the reaction dissolvent of described reaction is selected from the group be made up of DMF, N, N-diethylformamide, dimethyl sulfoxine, oxolane.Particularly preferably, the reaction dissolvent of described reaction is selected from DMF or N, N-diethylformamide.The reaction temperature of described reaction is preferably-20 DEG C ~ 80 DEG C; More preferably, the reaction temperature of described reaction is 0 DEG C ~ 50 DEG C; More preferably, the reaction temperature of described reaction is room temperature.
In an embodiment of the invention, in described step (3) the second drug molecule or through blocking group modify drug molecule and formula II compound addition be 1: 0.5-2 in molar ratio.Due to the second drug molecule in step (3) or through blocking group modify drug molecule can only with the leaving group generation nucleophilic substitution of in formula II compound, therefore in step (3) the second drug molecule or through blocking group modify drug molecule and the unnecessary formula II compound that makes of formula II compound addition be in the excessive state added.Preferably; described step (3) Chinese medicine molecule or be 1: 0.5-1.5 in molar ratio through drug molecule and formula II compound addition that blocking group is modified, the drug molecule described in more preferred or be 1: 0.5-1 in molar ratio through the drug molecule of blocking group modification and formula II compound addition.
In an embodiment of the invention, described step (3) neutral and alkali condition is under NaH alkali condition.The addition of described NaH is the second drug molecule or the drug molecule modified through blocking group is 1: 1-5 with NaH in molar ratio, is preferably 1: 2-4, more preferably 1: 2-3.
Optional, also include step (4) in the preparation method of a kind of Polyethylene Glycol-drug molecular bond of the present invention, slough the protecting group through the drug molecule group of blocking group modification in the compound of general formula I I.Preferably, described step (4) is by the compound dissolution of general formula III, passes into hydrogen chloride gas precursor reactant, after reaction, adds wet chemical and regulates pH to be 7-10, be separated to obtain product.
In a specific embodiment of the present invention, the compound of described general formula III
for having
the compound of structure, wherein Y is H or blocking group.Preferably, described blocking group is methoxvethoxvmethvl (MEM-).Particularly preferred, the compound of described general formula III
be selected from the compound of following E α, E β, D α, D beta structure:
In a specific embodiment of the present invention, the preparation method of described Polyethylene Glycol-drug molecular bond, comprising: (1) is by HO-CH
2-(CH
2oCH
2)
n-CH
2-OH dissolves, and adds toluene sulfochloride, cooling, adds KOH and reacts 1-8 hour, be separated the compound obtaining formula I
(2) be dissolved in DMAc by the compound of general formula C1 or C2, cooling, adds NaH in batches, then adds the DMAc solution of compound of formula I, room temperature reaction, is separated the compound obtaining general formula I I after reaction
the addition of the compound of its formula of C1 or C2 and the compound of general formula I I is 1: 1-2 in molar ratio; (3) be dissolved in DMAc by the compound of general formula C1 or C2, cooling, adds NaH in batches, then adds the DMAc solution of compound of general formula I I, room temperature reaction, is separated the compound obtaining general formula III after reaction
optional, (4) are by the compound of general formula III
rong Xie, passes into hydrogen chloride gas precursor reactant, after reaction, adds wet chemical and regulates pH to be 7-10, be separated to obtain product.
Another aspect of the invention additionally provides the compound of a kind of general formula I I
and the salt to be formed with mineral acid or organic acid.
Wherein, n is the integer of 0-20,
Described L is leaving group, be selected from by
the group of-F ,-I ,-Br and-Cl composition;
Described X
1the drug molecule group being the first drug molecule or modifying through blocking group.
Containing the leaving group that can react with drug molecule further in the compound one side structure of general formula I I of the present invention, thus can as the intermediate preparing Polyethylene Glycol-drug molecular bond; In structure, there is pharmaceutically active molecular radical on the other hand, can be separated in vivo and independently play pharmaceutically active effect.
In an embodiment of the invention, the described salt formed with mineral acid or organic acid, can be hydrochlorate, hydrobromate, sulfate, nitrate, phosphate, citrate, tartrate, fumarate, maleate, lactate, benzene sulfonate, pantothenate, Ascorbate etc., also can be the combination of above-mentioned salt.
In a specific embodiment of the present invention, the compound of described general formula I I is:
or
and the salt to be formed with mineral acid or organic acid, wherein, Y is H or blocking group.Preferably, described blocking group is methoxvethoxvmethvl (MEM-).
Polyethylene Glycol of the present invention-drug molecule conjugate preparation method can reduce side reaction by two-step method reaction, the total recovery of Polyethylene Glycol-drug molecular bond is increased to more than 40%, reaction condition is more easily controlled, there is very strong industrial applicibility.Meanwhile, the compound of general formula I I of the present invention not only as the intermediate preparing Polyethylene Glycol-drug molecular bond but also can independently play pharmaceutically active effect, and in its preparation feedback process, productive rate can reach more than 90%.
Detailed description of the invention
Following examples are only used for the present invention is described, are not used for limiting the present invention.
Naloxone hydrochloride used in embodiment is provided by Beijing Yi Dong BOJOD Science Co., Ltd, 2-methoxvethoxvmethvl chlorine (MEMCl) is buied from alfaAesar, paratoluensulfonyl chloride is buied from Shandong hundred million Yilong Industry Co., Ltd., sodium hydride slave ladder is uncommon likes that (Shanghai) changes into industrial development company limited and buys, H (OCH
2cH
2)
4oH, H (OCH
2cH
2)
5oH, H (OCH
2cH
2)
6oH, H (OCH
2cH
2)
7oH, H (OCH
2cH
2)
9oH buys from Jiaxing Bo Mei Bioisystech Co., Ltd.Other reagent used in the embodiment of the present invention is commercial chemical pure reagent.
embodiment 1
The preparation of MEM-6 α-naloxol (Compound C 1)
The preparation of MEM-naloxone (compd B):
Naloxone hydrochloride (60.0g, 0.15mol) is dissolved in CH
2cl
2(2.0L) in, add diisopropylethylamine (DIPEA) (96.9g, 0.75mol), then add 2-methoxvethoxvmethvl chlorine (MEMCl) (74.7g, 0.60mol).Reactant mixture at room temperature stirs 18h, adds water and extracts 3 times (500mL × 3).Organic facies saturated nacl aqueous solution washing (500mL), adds anhydrous sodium sulfate drying, filters.Concentrating under reduced pressure, column chromatography obtains colourless viscous liquid MEM-naloxone 55.0g, yield 88.3%.
1HNMR(CDCl
3，400Mz)：δ6.91(d，1H)，6.63(d，1H)，5.82(m，1H)，5.19(m，4H)，5.02(brd，1H)，4.66(s，1H)，3.89(m，2H)，3.57(m，2H)，3.37(s，3H)，3.17-2.97(m，5H)，2.58(m，2H)，2.39(m，1H)，2.29(m，1H)，2.14(m，1H)，1.86(m，1H)，1.61(m，2H)。
The preparation of MEM-6 α-naloxol (Compound C 1):
MEM-naloxone (80.0g, 0.19mol) is dissolved in MeOH (2.0L), adds NaBH (OAc)
3(120.8g, 0.57mol) and AcOH (34.2g, 0.57mol).Reactant mixture at room temperature stirs 12h, with aqueous sodium carbonate, reactant liquor is adjusted to pH=8, all solvents of decompression removing.Residue is dissolved in CH
2cl
2(1.0L), in, with the saturated NaCl aqueous solution extraction 3 times (1.0L × 3) of 0.1NHCl, combining water layer, uses CH
2cl
2wash 3 times (1.0L × 3).With aqueous sodium carbonate, water layer is adjusted to pH=8, uses CH
2cl
2extract 3 times (1.0L × 3).Merge organic layer, add anhydrous sodium sulfate drying, filter.Removal of solvent under reduced pressure, residue is dried overnight in a vacuum, obtains colourless viscous liquid MEM-6 α-naloxol 64.8g, yield 81.7%.
1HNMR(CDCl
3，400Mz)：δ6.84(d，1H)，6.59(d，1H)，5.80(m，1H)，5.56(d，1H)，5.17(m，2H)，5.13(d，1H)，4.88(brd，1H)，4.61(d，1H)，4.17(m，1H)，3.86(m，2H)，3.54(m，2H)，3.36(s，3H)，3.12-2.89(m，5H)，2.58(m，2H)，2.21(m，2H)，1.84(m，1H)，1.52(m，3H)，1.31(m，1H)。
embodiment 2
The preparation of MEM-6 β-naloxol (Compound C 2)
The preparation of MEM-6 β-naloxol Nitrodracylic acid ester (Compound C Z):
By MEM-6 α-naloxol (50.0g, 0.12mol), triphenylphosphine (62.9g, 0.24mol) with Nitrodracylic acid (40.1g, 0.24mol) be dissolved in dry toluene (1.5L), dry toluene (150mL) solution of diethyl azodiformate (DEAD) (41.8g, 0.24mol) is instilled in 20min.Reactant mixture at room temperature stirs 12h, filters.Removal of solvent under reduced pressure, residue is dissolved in the aqueous solution (1.5L) of D-tartaric acid (27.0g, 0.18mol), washs 3 times (500mL × 3) with methyl tertiary butyl ether(MTBE).Water layer with 10% NH
3h
2o is basified to pH=8, uses CH
2cl
2extract 3 times (1.0L × 3).Mixing organic layer is with brine It (1.5L), and distilled water wash (1.5L), anhydrous sodium sulfate drying, filters.Removal of solvent under reduced pressure, residue is separated through post and obtains light yellow solid MEM-6 β-naloxol Nitrodracylic acid ester 53.2g, yield 78.2%.
The preparation of MEM-6 β-naloxol (Compound C 2):
MEM-6 β-naloxol Nitrodracylic acid ester (50.0g, 88.2mmol) is dissolved in methanol (1.0L), adds K
2cO
3(51.1g, 0.37mol) and distilled water (70mL), return stirring reaction 3.5h.Cooling, removal of solvent under reduced pressure, adds ethyl acetate (1.0L), with distilled water wash 3 times (500mL × 3), anhydrous sodium sulfate drying, filters.Removal of solvent under reduced pressure, residue is separated through post and obtains colourless viscous liquid MEM-6 β-naloxol 35.3g, yield 95.8%.
1HNMR(CDCl
3，400Mz)：δ6.90(d，1H)，6.61(d，1H)，5.80(m，1H)，5.25(m，4H)，4.97(brd，1H)，4.47(d，1H)，4.04(m，1H)，3.78(m，1H)，3.58(m，2H)，3.38(m，1H)，3.36(s，3H)，3.11(m，2H)，3.06(m，1H)，2.92(m，1H)，2.62(m，2H)，2.17(m，2H)，1.95(m，1H)，1.60(m，2H)，1.48(m，1H)，1.34(m，1H)。
embodiment 3
MEM-naloxol-6 α-O-PEG
5the preparation of-OTs (Compound I α 5)
TsO-PEG
5the preparation of-OTs (Compound II per 5):
Five glycol (20.0g, 83.9mmol) are dissolved in CH
2cl
2(100mL) in, add paratoluensulfonyl chloride (32.0g, 167.8mmol), ice-water bath is cooled to 0 DEG C.Slowly add KOH (37.6g, 671.2mmol), control temperature of reaction system lower than 5 DEG C.Reactant liquor stirs 3h at 0 DEG C, adds CH
2cl
2(100mL) with frozen water (200mL).Separate organic facies, aqueous phase CH
2cl
2extract 2 times (100mL × 2).Mixing organic phase washed with water (100mL), anhydrous sodium sulfate drying, removal of solvent under reduced pressure, residue is separated to obtain colourless liquid TsO-PEG through post
5-OTs43.3g, yield 94.5%.
1HNMR(CDCl
3，400Mz)：δ7.79(d，4H)，7.34(d，4H)，4.15(m，4H)，3.68(m，4H)，3.59(m，12H)，2.44(s，6H)。
MEM-naloxol-6 α-O-PEG
5the preparation of-OTs (Compound I α 5):
Be dissolved in by MEM-6 α-naloxol (2.18g, 5.22mmol) in DMAc (20mL), ice bath stirs and is cooled to 0 DEG C under nitrogen protection.Add NaH (60%, 0.63g, 15.66mmol) in batches, after stirring 30min, add TsO-EG again
5dMAc (10mL) solution of-OTs (5.71g, 10.44mmol).Dropwise, room temperature reaction stirs and spends the night.In reactant liquor, add frozen water (10mL) cancellation reaction, add saturated aqueous common salt (500mL), use CH
2cl
2extract 3 times (500mL × 3).Collect organic facies, with saturated common salt water washing 3 times (500mL × 3), add anhydrous sodium sulfate drying, filter.Removal of solvent under reduced pressure, residue is separated through post and obtains pale yellow viscous liquid MEM-naloxol-6 α-O-PEG
5-OTs3.70g, yield 89.6%.
LC-MS[M+H]
+：793.0。
1HNMR(CDCl
3，400Mz)：δ7.80(d，2H)，7.34(d，2H)，6.91(d，1H)，6.54(d，1H)，5.78(m，1H)，5.22(m，4H)，4.88(brd，1H)，4.71(d，1H)，4.16(m，2H)，3.95-3.50(m，23H)，3.36(s，3H)，3.11-2.88(m，5H)，2.56(m，2H)，2.45(s，3H)，2.22-1.26(m，6H)。
embodiment 4
MEM-naloxol-6 β-O-PEG
5the preparation of-OTs (Compound I β 5)
Replace MEM-6 α-naloxol with MEM-6 β-naloxol, the step repeating embodiment 3 obtains MEM-naloxol-6 β-O-PEG
5-OTs, yield 85.2%.
LC-MS[M+H]
+：793.0。
1HNMR(CDCl
3，400Mz)：δ7.81(d，2H)，7.35(d，2H)，6.92(d，1H)，6.60(d，1H)，5.77(m，1H)，5.29(m，2H)，5.17(m，2H)，4.84(brd，1H)，4.53(d，1H)，4.16(m，2H)，3.89-3.50(m，23H)，3.36(s，3H)，3.21-2.88(m，5H)，2.54(m，2H)，2.45(s，3H)，2.19-1.24(m，6H)。
embodiment 5
MEM-naloxol-6 α-O-PEG
7the preparation of-OMs (Compound I β 7)
MsO-PEG
7the preparation of-OMs (Compound II per 7-1):
By seven glycol (6.53g; 20mmol) be dissolved in anhydrous tetrahydro furan (500mL); ice-water bath is cooled to 0 DEG C; add the new triethylamine (8.10g steamed under nitrogen protection successively; 80mmol) with methane sulfonyl chloride (7.33g; 64mmol), controlling rate of addition makes temperature of reaction system be no more than 5 DEG C.Rise to room temperature after dropwising, and at room temperature stirring is spent the night.Decompression removing oxolane, adds distilled water (40mL) to residue, uses CH
2cl
2extract in 3 times (150mL × 3), organic facies uses 0.1NHCl (80mL × 3) and distilled water (80mL × 2) washing successively, with anhydrous sodium sulfate drying, filters.Removal of solvent under reduced pressure, obtains colourless liquid MsO-PEG
7-OMs9.55g, yield 99.0%.
1HNMR(CDCl
3，400Mz)：δ4.39-4.36(m，4H)，3.77-3.62(m，24H)，3.08(s，6H)。
MEM-naloxol-6 α-O-PEG
7the preparation of-OMs (Compound I α 7):
Use MsO-PEG
7-OMs replaces TsO-PEG
5-OTs, the step repeating embodiment 3 obtains MEM-naloxol-6 α-O-PEG
7-OMs, yield 83.7%.
LC-MS[M+H]
+：804.4。
1HNMR(CDCl
3，400Mz)：δ6.91(d，1H)，6.54(d，1H)，5.78(m，1H)，5.22(m，4H)，4.88(brd，1H)，4.71(d，1H)，4.37(m，2H)，3.95-3.50(m，31H)，3.36(s，3H)，3.11-2.88(m，8H)，2.56(m，2H)，2.22-1.26(m，6H)。
embodiment 6
MEM-naloxol-6 β-O-PEG
7the preparation of-Br (Compound I β 7)
Br-PEG
7the preparation of-Br (Compound II per 7-2):
By the MsO-PEG prepared according to embodiment 5 method
7-OMs (9.55g, 19.8mmol) and tetra-n-butyl ammonium bromide (25.60g, 79.4mmol) are dissolved in acetonitrile (50mL), under nitrogen protection 50 DEG C of insulated and stirred 15h.Be cooled to room temperature, removal of solvent under reduced pressure.Residue is dissolved in distilled water (150mL), is extracted with ethyl acetate 2 times (200mL × 2).Mixing organic facies distilled water wash 2 times (100mL × 2), anhydrous sodium sulfate drying, filters.Removal of solvent under reduced pressure, obtains red liquid Br-PEG
7-Br7.83g, yield 87.4%.
1HNMR(CDCl
3，400Mz)：δ3.82-3.77(m，4H)，3.65(m，20H)，3.48-3.44(m，4H)。
MEM-naloxol-6 β-O-PEG
7the preparation of-Br (Compound I β 7):
Use Br-PEG
7-Br replaces TsO-PEG
5-OTs, the step repeating embodiment 4 obtains MEM-naloxol-6 β-O-PEG
7-Br, yield 78.3%.
LC-MS[M+H]
+：789.3。
1HNMR(CDCl
3，400Mz)：δ6.92(d，1H)，6.60(d，1H)，5.77(m，1H)，5.29(m，2H)，5.17(m，2H)，4.84(brd，1H)，4.53(d，1H)，3.89-3.50(m，31H)，3.45(m，2H)，3.36(s，3H)，3.21-2.88(m，5H)，2.54(m，2H)，2.19-1.24(m，6H)。
embodiment 7
MEM-naloxol-6 β-O-PEG
9the preparation of-OTs (Compound I β 9)
Replace five glycol with nine glycol, the step repeating embodiment 4 obtains MEM-Na Luo-6 β-O-PEG
9-OTs, yield 81.9%.
LC-MS[M+H]
+：969.1。
1HNMR(CDCl
3，400Mz)：δ7.81(d，2H)，7.35(d，2H)，6.92(d，1H)，6.60(d，1H)，5.77(m，1H)，5.29(m，2H)，5.17(m，2H)，4.84(brd，1H)，4.53(d，1H)，4.16(m，2H)，3.89-3.50(m，39H)，3.36(s，3H)，3.21-2.88(m，5H)，2.54(m，2H)，2.45(s，3H)，2.19-1.24(m，6H)。
embodiment 8
Use MEM-naloxol-6 α-O-PEG
5-OTs (Compound I α 5) prepares naloxol-6 α-O-PEG
5-O-6 α-naloxol (compd E α 5)
MEM-naloxol-6 α-O-PEG
5the preparation of-O-6 α-naloxol-MEM (Compound D α 5):
Be dissolved in by MEM-6 α-naloxol (2.14g, 5.12mmol) in DMAc (20mL), ice bath stirs and is cooled to 0 DEG C under nitrogen protection.Add NaH (60%, 0.41g, 10.23mmol) in batches, after stirring 30min, add MEM-naloxol-6 α-O-PEG again
5dMAc (10mL) solution of-OTs (2.70g, 3.41mmol).Dropwise, room temperature reaction stirs and spends the night.In reactant liquor, add frozen water (10mL) cancellation reaction, add saturated aqueous common salt (500mL), use CH
2cl
2extract 3 times (500mL × 3).Collect organic facies, with saturated common salt water washing 3 times (500mL × 3), add anhydrous sodium sulfate drying, filter.Removal of solvent under reduced pressure, residue is separated through post and obtains pale yellow viscous liquid MEM-naloxol-6 α-O-PEG
5-O-6 α-naloxol-MEM2.23g, yield 63.1%.With MEM-6 α-naloxol for initiation material, the total recovery through two-step reaction is 48.2%.LC-MS[M+H]
+：1038.1。
1HNMR(CDCl
3，400Mz)：δ6.91(d，2H)，6.53(d，2H)，5.78(m，2H)，5.22(m，8H)，4.88(d，2H)，4.71(d，2H)，3.94-3.50(m，32H)，3.37(s，6H)，3.07(m，6H)，2.88(m，2H)，2.56(m，4H)，2.20(m，4H)，1.60-1.26(m，8H)。
Naloxol-6 α-O-PEG
5the preparation of-O-6 α-naloxol (compd E α 5):
By MEM-naloxol-6 α-O-PEG
5-O-6 α-naloxol-MEM (1.52g, 1.47mmol) is dissolved in oxolane (30mL), adds the tetrahydrofuran solution (20mL) of 4NHCl, stirred overnight at room temperature.Removal of solvent under reduced pressure, adds distilled water (30mL), uses CH in residue
2cl
2wash 4 times (15mL × 4), aqueous phase saturated sodium bicarbonate adjusts pH=7-8, uses CH
2cl
2extract 3 times (30mL × 3).Collect organic facies, with anhydrous sodium sulfate drying, filter.Removal of solvent under reduced pressure obtains thick white solid naloxol-6 α-O-PEG
5-O-6 α-naloxol, yield 93.5%.
LC-MS[M/2+H]
+：431.1。
1HNMR(CDCl
3，400Mz)：δ6.71(d，2H)，6.50(d，2H)，5.80(m，2H)，5.17(m，4H)，4.71(d，2H)，3.89(m，2H)，3.80-3.50(m，22H)，3.06(m，6H)，2.88(m，2H)，2.57(m，4H)，2.22(m，4H)，1.72-1.42(m，8H)，1.19(m，2H)。
embodiment 9
Use MEM-naloxol-6 β-O-PEG
5-OTs (Compound I β 5) prepares naloxol-6 β-O-PEG
5-O-6 β-naloxol (compd E β 5)
MEM-naloxol-6 β-O-PEG
5the preparation of-O-6 β-naloxol-MEM (Compound D β 5):
MEM-6 α-naloxol is replaced, with MEM-naloxol-6 β-O-PEG with MEM-6 β-naloxol
5-OTs replaces MEM-naloxol-6 β-O-PEG
5-OTs, the step repeating embodiment 8 obtains MEM-naloxol-6 β-O-PEG
5-O-6 β-naloxol-MEM, yield 59.7%.With MEM-6 β-naloxol for initiation material, the total recovery through two-step reaction is 44.7%.LC-MS[M+H]
+：1038.1。
1HNMR(CDCl
3，400Mz)：δ6.91(d，2H)，6.59(d，2H)，5.77(m，2H)，5.21(m，8H)，4.53(d，2H)，3.88-3.54(m，28H)，3.36(s，6H)，3.20(m，2H)，3.11(m，4H)，3.05(m，2H)，2.89(m，2H)，2.54(m，4H)，2.20-1.20(m，14H)。
Naloxol-6 β-O-PEG
5the preparation of-O-6 β-naloxol (compd E β 5):
With MEM-naloxol-6 β-O-PEG
5-O-6 β-naloxol-MEM replaces MEM-naloxol-6 α-O-PEG
5-O-6 α-naloxol-MEM, the step repeating embodiment 8 obtains naloxol-6 β-O-PEG
5-O-6 β-naloxol, yield 92.2%.LC-MS[M/2+H]
+：431.1。
1HNMR(CDCl
3，400Mz)：δ6.64(d，2H)，6.48(d，2H)，5.71(m，2H)，5.10(m，4H)，4.47(d，2H)，3.80-3.50(m，22H)，3.16(m，2H)，2.99(m，6H)，2.82(m，2H)，2.47(m，4H)，2.08(m，4H)，1.85-1.15(m，10H)。
embodiment 10
Use MEM-naloxol-6 α-O-PEG
7-OMs (Compound I α 7) prepares naloxol-6 α-O-PEG
7-O-6 α-naloxol (compd E α 7)
MEM-naloxol-6 α-O-PEG
7the preparation of-O-6 α-naloxol-MEM (Compound D α 7):
With MEM-naloxol-6 α-O-PEG
7-OMs replaces MEM-naloxol-6 α-O-PEG
5-OTs, the step repeating embodiment 8 obtains MEM-naloxol-6 α-O-PEG
7-O-6 α-naloxol-MEM, yield 61.4%.With MEM-6 α-naloxol for initiation material, the total recovery through two-step reaction is 45.6%.LC-MS[M/2+H]
+：563.1。
1HNMR(CDCl
3，400Mz)：δ6.91(d，2H)，6.53(d，2H)，5.78(m，2H)，5.22(m，8H)，4.88(d，2H)，4.71(d，2H)，3.94-3.50(m，40H)，3.37(s，6H)，3.07(m，6H)，2.88(m，2H)，2.56(m，4H)，2.20(m，4H)，1.60-1.26(m，8H)。
Naloxol-6 α-O-PEG
7the preparation of-O-6 α-naloxol (compd E α 7):
With MEM-naloxol-6 α-O-PEG
7-O-6 α-naloxol-MEM replaces MEM-Na Luo-6 α-O-PEG
5-O-6 α-naloxol-MEM, the step repeating embodiment 8 obtains naloxol-6 α-O-PEG
7-O-6 α-naloxol, yield 90.6%.
LC-MS[M+H]
+：950.5。
1HNMR(CDCl
3，400Mz)：δ6.71(d，2H)，6.50(d，2H)，5.80(m，2H)，5.17(m，4H)，4.71(d，2H)，3.89(m，2H)，3.80-3.50(m，30H)，3.06(m，6H)，2.88(m，2H)，2.57(m，4H)，2.22(m，4H)，1.72-1.42(m，8H)，1.19(m，2H)。
embodiment 11
Use MEM-naloxol-6 β-O-PEG
7-Br (Compound I β 7) prepares naloxol-6 β-O-PEG
7-O-6 β-naloxol (compd E β 7)
MEM-naloxol-6 β-O-PEG
7the preparation of-O-6 β-naloxol-MEM (Compound D β 7):
MEM-6 α-naloxol is replaced, with MEM-naloxol-6 β-O-PEG with MEM-6 β-naloxol
7-Br replaces MEM-naloxol-6 α-O-PEG
5-OTs, the step repeating embodiment 8 obtains MEM-naloxol-6 β-O-PEG
7-O-6 β-naloxol-MEM, yield 56.3%.With MEM-6 β-naloxol for initiation material, the total recovery through two-step reaction is 42.6%.LC-MS[M/2+H]
+：563.1。
1HNMR(CDCl
3，400Mz)：δ6.91(d，2H)，6.59(d，2H)，5.77(m，2H)，5.21(m，8H)，4.53(d，2H)，3.88-3.54(m，38H)，3.36(s，6H)，3.20(m，2H)，3.11(m，4H)，3.05(m，2H)，2.89(m，2H)，2.54(m，4H)，2.20-1.20(m，14H)。
Naloxol-6 β-O-PEG
7the preparation of-O-6 β-naloxol (compd E β 7):
With MEM-naloxol-6 β-O-PEG
7-O-6 β-naloxol-MEM replaces MEM-Na Luo-6 α-O-PEG
5-O-6 α-naloxol-MEM, the step repeating embodiment 8 obtains naloxol-6 β-O-PEG
7-O-6 β-naloxol, yield 89.5%.
LC-MS[M+H]
+：950.5。
1HNMR(CDCl
3，400Mz)：δ6.64(d，2H)，6.48(d，2H)，5.71(m，2H)，5.10(m，4H)，4.47(d，2H)，3.80-3.50(m，30H)，3.16(m，2H)，2.99(m，6H)，2.82(m，2H)，2.47(m，4H)，2.08(m，4H)，1.85-1.15(m，10H)。
embodiment 12
Use MEM-naloxol-6 β-O-PEG
9-OTs (Compound I β 9) prepares naloxol-6 β-O-PEG
9-O-6 β-naloxol (compd E β 9)
MEM-naloxol-6 β-O-PEG
9the preparation of-O-6 β-naloxol-MEM (Compound D β 9):
MEM-6 α-naloxol is replaced, with MEM-naloxol-6 β-O-PEG with MEM-6 β-naloxol
9-OTs replaces MEM-naloxol-6 α-O-PEG
5-OTs, the step repeating embodiment 8 obtains MEM-naloxol-6 β-O-PEG
9-O-6 β-naloxol-MEM, yield 52.7%.With MEM-6 β-naloxol for initiation material, the total recovery through two-step reaction is 38.7%.LC-MS[M/2+H]
+：607.5。
1HNMR(CDCl
3，400Mz)：δ6.91(d，2H)，6.59(d，2H)，5.77(m，2H)，5.21(m，8H)，4.53(d，2H)，3.88-3.54(m，46H)，3.36(s，6H)，3.20(m，2H)，3.11(m，4H)，3.05(m，2H)，2.89(m，2H)，2.54(m，4H)，2.20-1.20(m，14H)。
The preparation of naloxol-6 β-O-PEG9-O-6 β-naloxol (compd E β 9):
With MEM-naloxol-6 β-O-PEG
9-O-6 β-naloxol-MEM replaces MEM-naloxol-6 α-O-PEG
5-O-6 α-naloxol-MEM, the step repeating embodiment 8 obtains naloxol-6 β-O-PEG
7-O-6 β-naloxol, yield 87.1%.LC-MS[M/2+H]
+：519.4。
1HNMR(CDCl
3，400Mz)：δ6.64(d，2H)，6.48(d，2H)，5.71(m，2H)，5.10(m，4H)，4.47(d，2H)，3.80-3.50(m，38H)，3.16(m，2H)，2.99(m，6H)，2.82(m，2H)，2.47(m，4H)，2.08(m，4H)，1.85-1.15(m，10H)。
Claims (18)
1. a preparation method for Polyethylene Glycol-drug molecule conjugate, is characterized in that, comprising: (1) is with HO-CH
2-(CH
2oCH
2)
n-CH
2-OH is the compound that reactant prepares formula I
(2) by drug molecule or through blocking group modify drug molecule and formula I shown in compound in the basic conditions nucleo philic substitution reaction obtain the compound of general formula II
Wherein, n is the integer of 0-20;
Described L is leaving group, be selected from by
the group of-F ,-I ,-Br and-Cl composition;
Described X
1the the first drug molecule group being the first drug molecule group or modifying through blocking group.
2. the preparation method of Polyethylene Glycol according to claim 1-drug molecule conjugate, is characterized in that, n is the integer of 1-15; More preferably, n is the integer of 2-10; More preferably, n is the integer of 4-9.
3. the preparation method of the Polyethylene Glycol described in any one of claim 1-2-drug molecule conjugate, is characterized in that, containing-OH group in the first described drug molecule or the first drug molecule of modifying through blocking group.
4. the preparation method of Polyethylene Glycol according to claim 3-drug molecule conjugate, it is characterized in that, the first described drug molecule is selected from opioid antagonist, oxymorphone, codeine, OxyContin, morphine, ethylmorphine hydrochloride, diacetylmorphine, hydromorphone, paracodin, paramorphane and methyldihydromorphine; Described opioid antagonist is selected from naloxone, N-methylnaloxone, 6-amino-14-hydroxyl-17-allyl Jino desomorphine, receive bent grace diindyl, Naltrexone, MNTX, Naboo sweet smell, butorphanol, Cyc, pentazocine, nalorphine, receive that bent grace diindyl, Naltrindole, promise third Na Tuofeimin, oxilorphan, 6-amino-6-deoxidation-naloxone, pentazocine, levallorphan methyl naltrexone, buprenorphine, plug clo are all, levallorphan and nalorphine.
5. the preparation method of Polyethylene Glycol according to claim 4-drug molecule conjugate, is characterized in that, described drug molecule or the drug molecule through blocking group modification are:
or
wherein MEM is methoxvethoxvmethvl.
6. the preparation method of the Polyethylene Glycol described in any one of claim 1-5-drug molecule conjugate, is characterized in that, described step (2) is reacted in polar non-solute, and reaction temperature is-20 DEG C ~ 100 DEG C.
7. the preparation method of the Polyethylene Glycol described in any one of claim 1-6-drug molecule conjugate, it is characterized in that, the reaction dissolvent of described reaction is selected from by N, the group of dinethylformamide, N, N-diethylformamide, dimethyl sulfoxine, hexamethyl phosphoramide, N-Methyl pyrrolidone, oxolane, acetone, dioxane, acetonitrile, dichloromethane, chloroform composition; More preferably, the reaction dissolvent of described reaction is selected from the group be made up of DMF, N, N-diethylformamide, dimethyl sulfoxine, oxolane; The reaction temperature of described reaction is-20 DEG C ~ 80 DEG C.
8. the preparation method of the Polyethylene Glycol described in any one of claim 1-7-drug molecule conjugate; it is characterized in that; described step (2) Chinese medicine molecule or through blocking group modify drug molecule and formula I addition be 1:1-4 in molar ratio; preferably; described step (2) Chinese medicine molecule or be 1:1-3 in molar ratio through drug molecule and formula I addition that blocking group is modified, the drug molecule described in more preferred or be 1:1-2 in molar ratio through the drug molecule of blocking group modification and formula II compound addition.
9. the active combination of Polyethylene Glycol and naloxol and the salt that formed with mineral acid or organic acid thereof, it is characterized in that, described active combination has general formula II structure:
Wherein, n is the integer of 0-20,
Described L is leaving group, be selected from by
the group of-F ,-I ,-Br and-Cl composition;
Described X
1the drug molecule group being the first drug molecule group or modifying through blocking group.
10. Polyethylene Glycol according to claim 9-drug molecule conjugate and the salt that formed with mineral acid or organic acid thereof, it is characterized in that, n is the integer of 1-15; More preferably, n is the integer of 2-10; More preferably, n is the integer of 4-9.
Polyethylene Glycol described in 11. any one of claim 9-10-drug molecule conjugate and the salt formed with mineral acid or organic acid thereof, it is characterized in that, described drug molecule is selected from opioid antagonist, oxymorphone, codeine, OxyContin, morphine, ethylmorphine hydrochloride, diacetylmorphine, hydromorphone, paracodin, paramorphane and methyldihydromorphine; Described opioid antagonist is selected from naloxone, N-methylnaloxone, 6-amino-14-hydroxyl-17-allyl Jino desomorphine, receive bent grace diindyl, Naltrexone, MNTX, Naboo sweet smell, butorphanol, Cyc, pentazocine, nalorphine, receive that bent grace diindyl, Naltrindole, promise third Na Tuofeimin, oxilorphan, 6-amino-6-deoxidation-naloxone, pentazocine, levallorphan methyl naltrexone, buprenorphine, plug clo are all, levallorphan and nalorphine.
12. Polyethylene Glycol according to claim 11-drug molecule conjugates and the salt formed with mineral acid or organic acid thereof, it is characterized in that, described active combination is
and the salt to be formed with mineral acid or organic acid, wherein, Y is H or blocking group.
13. Polyethylene Glycol according to claim 12-drug molecule conjugates and the salt formed with mineral acid or organic acid thereof, it is characterized in that, the blocking group in described Y is methoxvethoxvmethvl.
Polyethylene Glycol described in 14. any one of claim 9-13-drug molecule conjugate and the salt formed with mineral acid or organic acid thereof, it is characterized in that, the described salt formed with mineral acid or organic acid is hydrochlorate, hydrobromate, sulfate, nitrate, phosphate, citrate, tartrate, fumarate, maleate, lactate, benzene sulfonate, pantothenate or Ascorbate.
The preparation method of 15. 1 kinds of Polyethylene Glycol-drug molecular bond, is characterized in that, comprising:
(1) with HO-CH
2-(CH
2oCH
2)
n-CH
2-OH is the compound that reactant prepares formula I
(2) by the first drug molecule or through blocking group modify drug molecule and formula I shown in compound in the basic conditions nucleo philic substitution reaction obtain the compound of general formula II
(3) by the second drug molecule or through blocking group modify drug molecule and general formula II compound in the basic conditions nucleo philic substitution reaction obtain the compound of general formula III
Wherein, n is the integer of 0-20;
Described L is leaving group, be selected from by
the group of-F ,-I ,-Br and-Cl composition;
Described X
1the the first drug molecule group being the first drug molecule group or modifying through blocking group; X
2the the second drug molecule group being the second drug molecule or modifying through blocking group.
The preparation method of 16. a kind of Polyethylene Glycol-drug molecular bond according to claim 15; it is characterized in that, the first drug molecule or through blocking group modify drug molecule group and the second drug molecule or through blocking group modify drug molecule be selected from the compound with formula C1 or C2:
or
wherein MEM is methoxvethoxvmethvl.
The preparation method of 17. a kind of Polyethylene Glycol-drug molecular bond according to claim 16, it is characterized in that, the compound of described general formula III is
wherein Y is H or methoxvethoxvmethvl.
The preparation method of 18. Polyethylene Glycol according to claim 17-drug molecular bond, the compound of described general formula III is selected from following compound:
or
Or
or
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016086846A1 (en) * | 2014-12-05 | 2016-06-09 | 北京键凯科技有限公司 | Conjugate of polyethylene glycol and pharmaceutical molecule and preparation method thereof |
| WO2017129046A1 (en) * | 2016-01-29 | 2017-08-03 | 北京键凯科技股份有限公司 | Pegylated opioid with low addictive effect |
| CN107033154A (en) * | 2016-02-02 | 2017-08-11 | 苏州派格生物科技有限公司 | Opiate receptor antagonist conjugate and its application |
| WO2018113581A1 (en) * | 2016-12-22 | 2018-06-28 | 北京键凯科技股份有限公司 | Conjugate of dezocine and polyethylene glycol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019058387A1 (en) * | 2017-09-19 | 2019-03-28 | Msn Laboratories Private Limited, R&D Center | An improved process for the preparation of (5α,6α)-17-allyl-6-(2,5,8,11,14,17,20- heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol and its pharmaceutically acceptable salts |
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| CN103289075A (en) * | 2012-02-22 | 2013-09-11 | 天津键凯科技有限公司 | Conjugate of polyethylene glycol and naloxone, and pharmaceutical composition and applications thereof |
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| CN101732313A (en) * | 2008-11-25 | 2010-06-16 | 北京四环制药有限公司 | Medicine composition of naloxone hydrochloride and polyethylene glycol and preparation method thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016086846A1 (en) * | 2014-12-05 | 2016-06-09 | 北京键凯科技有限公司 | Conjugate of polyethylene glycol and pharmaceutical molecule and preparation method thereof |
| WO2017129046A1 (en) * | 2016-01-29 | 2017-08-03 | 北京键凯科技股份有限公司 | Pegylated opioid with low addictive effect |
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| CN107033154A (en) * | 2016-02-02 | 2017-08-11 | 苏州派格生物科技有限公司 | Opiate receptor antagonist conjugate and its application |
| CN107033154B (en) * | 2016-02-02 | 2020-02-04 | 上海瀚迈生物医药科技有限公司 | Opioid receptor antagonist conjugates and uses thereof |
| US11311533B2 (en) | 2016-02-02 | 2022-04-26 | Shanghai Hanmai Bio-Pharma Co., Ltd. | Opioid receptor antagonist conjugate and use thereof |
| WO2018113581A1 (en) * | 2016-12-22 | 2018-06-28 | 北京键凯科技股份有限公司 | Conjugate of dezocine and polyethylene glycol |
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