WO2019001473A1 - Dérivé de polyglycol dendritique, son procédé de préparation et son application - Google Patents

Dérivé de polyglycol dendritique, son procédé de préparation et son application Download PDF

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WO2019001473A1
WO2019001473A1 PCT/CN2018/093134 CN2018093134W WO2019001473A1 WO 2019001473 A1 WO2019001473 A1 WO 2019001473A1 CN 2018093134 W CN2018093134 W CN 2018093134W WO 2019001473 A1 WO2019001473 A1 WO 2019001473A1
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group
integer
dendritic
derivative
polyglycol
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Chinese (zh)
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主辉
林美娜
赵宣
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北京键凯科技股份有限公司
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Publication of WO2019001473A1 publication Critical patent/WO2019001473A1/fr
Priority to US16/729,882 priority Critical patent/US11053185B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/10—Saturated ethers of polyhydroxy compounds
    • C07C43/11—Polyethers containing —O—(C—C—O—)n units with ≤ 2 n≤ 10
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
    • C08G65/48—Polymers modified by chemical after-treatment

Definitions

  • the invention relates to the technical field of chemical industry, in particular to a dendritic polyglycol derivative and a preparation method and application thereof.
  • Dendritic (or dendritic) polymers are a class of non-linear polymers with highly branched structures that have excellent geometric symmetry and that the size and shape of the molecules can be precisely controlled. Due to the unique structure of the dendrimer, it has a series of unique physical and chemical properties such as low viscosity, high rheology and a large number of terminal functional groups which are not available in traditional linear polymers. In supramolecular chemistry, biomedicine, photochemistry , Electrochemistry, catalysts and other fields have broad application prospects.
  • PAMAM polyamide-amine dendrimer
  • PEG Polyethylene glycol
  • PEG40k modifies the 20-hydroxyl group of camptothecin, and the solubility of modified PEG-camptothecin in water is about 2 mg/mL, which is the solubility of the original drug camptothecin (0.0025 mg/mL). 800 times.
  • the lactone in the camptothecin structure and the tertiary alcohol in the 20 position are the basic active sites for inhibiting the topoisomerase.
  • the modification of the 20-hydroxyl group by PEG improves the water solubility of the drug and improves the stability of the lactone. And the drug is given anti-tumor targeting. Animal experiments have found that the drug concentration of the prodrug at the tumor site is 30 times that of camptothecin, which greatly improves its efficacy. At present, the drug has entered the clinical stage.
  • the modification of PEG to paclitaxel, scutellarin, etc. can also greatly enhance its water solubility, improve oil-water distribution, thereby increasing the efficacy, and PEG-modified prodrugs such as paclitaxel, doxorubicin and cytarabine Entered the clinical trial phase.
  • the inventors of the present invention have obtained a dendritic polyglycol derivative obtained by experiments and research, which has good water solubility and biocompatibility, and has very low toxicity, and can be used as a carrier for modifying poorly soluble drugs and improving At the same time of water solubility, since the dendritic polyglycol derivative has a plurality of terminal functional groups, the drug loading can be increased and the bioavailability can be improved.
  • the present invention provides a dendritic polyglycol derivative having the structure of formula (I):
  • a 1 , A 2 , D 1 and D 2 are the same or different YX-structures, or the same or different Structure; J, K are the same or different YX-structures;
  • R a1-4 , R b1-2 and R d1-4 ie R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R d1 , R d2 , R d3 and R d4
  • R j and R k is a linking group independently selected from: -(CH 2 ) r -, -(CR 1 R 2 ) r -, -(CH 2 ) r NH-, -NHCO(CH 2 ) r -, -( CH 2 ) r Combination of one or more of CONH- and -CO(CH 2 ) r -, r is an integer from 0 to 30 (specifically, 0, 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 15, 20, 25 or 30),
  • R 1 and R 2 are independently selected from: -H, C1-C6 alkyl, -OR', -NHR', -N(R') 2 , -CN, -F, -Cl, -Br, -I a combination of one or more of -COR', -COOR', -OCOR', -CONHR', and -CON(R') 2 ,
  • R' is selected from the group consisting of: -H, C1-C6 alkyl, -F, -Cl, -Br and -I,
  • Y is a terminal group selected from the group consisting of: C1-C6 alkyl group, C1-C6 alkoxy group, H (hydrogen atom), hydroxyl group, amino group, aminomethyl group, maleimide group, carboxyl group, ester group, fluorenyl group , succinimide carbonate, succinimide acetate, succinimide propionate, succinimide succinate, succinimidyl, dithiopyridyl, propionate, aldehyde, Anthranyl ester, acrylate group, acrylate group, azido group, glutaric acid group, hydrazide group, alkynyl group, p-nitrophenyl carbonate group, isocyanate group, silane group, carboxymethyl group, vinyl sulfone group And one of the vitamin H residues;
  • E 1-7 , E j and E k are the same or different polyglycol group (OCH 2 CH 2 ) m , m is an integer from 0 to 100 (specifically 0-20 (eg 0, 1, 2) , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), 30-50 (eg 30, 35, 40, 45 Or 50) or 50-100 (such as 50, 60, 70, 80, 90 or 100));
  • the A 1 , A 2 , D 1 and D 2 are the same or different
  • the dendritic polyglycol derivative may be an eight-arm dendritic polyglycol derivative.
  • i in the linking group X is 0, 1, 2, 3 or 4.
  • said A 1 , A 2 , D 1 and D 2 are independently selected from the group consisting of: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, -CH One of 2 CH 2 COOH and -CH 2 CH 2 N 3 .
  • said B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and - One of CH 2 CH 2 CH 2 CHO.
  • p is an integer from 0 to 5, such as 0, 1, 2, 3, 4 or 5.
  • said L 1-3 and L n have the structure of formula (II) or formula (III).
  • the L 1-3 and L n are independently selected from the group consisting of
  • the dendritic polyethylene glycol derivative has the following structure:
  • R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R b1 , R b2 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 and R d8 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more preferably an integer of 0 to 5, such as 0, 1. 2, 3, 4 and 5.
  • the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 have the structure of the formula (II) or the formula (III), more preferably from:
  • m in the polyglycol group (OCH 2 CH 2 ) m is an integer of 0-20, more preferably an integer of 0-12, and most preferably, m is 0. 1, 2, 3, 4, 5, 6, 7, or 8.
  • the X is selected from -(CH 2 ) i -, -CO(CH 2 ) i -, -( CH 2 ) a combination of one or more of i NH- and (CH 2 ) i CONH-, more preferably -(CH 2 ) i -; preferably, i in the linking group X is 0, 1, 2, 3 or 4; further preferably, the X is a single bond, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a thiol group, a carboxyl group, and an ester group.
  • a methoxy group a methoxy group
  • a hydroxyl group an amino group
  • an azide group a thiol group
  • a carboxyl group and an ester group.
  • an aldehyde group, an acryl group, and a maleimide group One of an aldehyde group, an acryl group, and a maleimide group.
  • the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and One of -CH 2 CH 2 CH 2 CHO; more specifically, the A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 One of -, -CH 2 CH 2 COOH and -CH 2 CH 2 N 3 .
  • the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 One of CH 2 CH 2 CHO.
  • the dendritic polyglycol derivative has the following structure:
  • M1-4 is independently selected from an integer from 0 to 100, specifically an integer from 0 to 20, particularly an integer from 0 to 12; in one embodiment of the invention, the m1-4 is 3.
  • the X is selected from -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 a combination of one or more of i NH- and (CH 2 ) i CONH-, more specifically -(CH 2 ) i -; in particular, i in the linking group X is 0, 1, 2 3 or 4;
  • the X is a single bond, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a thiol group, a carboxyl group, an ester group, and an aldehyde.
  • a group, an acryl group, and a maleimide group is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a thiol group, a carboxyl group, an ester group, and an aldehyde.
  • the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and -CH One of 2 CH 2 CH 2 CHO; further specifically, the A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, One of -CH 2 CH 2 COOH and -CH 2 CH 2 N 3 ; in one embodiment of the invention, the A 1 , A 2 , D 1 and D 2 are both -CH 3 .
  • the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 CH One of 2 CH 2 CHO; in one embodiment of the invention, the B is -OH.
  • the R a1 , R b1 and R d1 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more specifically, the R a1 , R b1 And R d1 are the same or different -(CH 2 ) r -, r is an integer of 0-5; in one embodiment of the invention, the R a1 , R b1 and R d1 are both -C 3 H 6 -.
  • the -R b1 -B is -C 3 H 6 -OH.
  • the dendritic polyglycol derivative has the following structure:
  • the dendritic polyglycol derivative has the following structure:
  • R a1 , R b1 , R d1 , A 1 , A 2 , D 1 , D 2 and B have the above definitions of the invention
  • M1-6 is independently selected from an integer from 0-100, such as an integer from 0-20, particularly an integer from 0 to 12; in one embodiment of the invention, the m1-6 is 3.
  • the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and -CH One of 2 CH 2 CH 2 CHO; further specifically, A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, -CH One of 2 CH 2 COOH and -CH 2 CH 2 N 3 ; in one embodiment of the invention, the A 1 , A 2 , D 1 and D 2 are both -CH 2 CH 2 NH 2 .
  • the R a1 , R b1 and R d1 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more specifically, the R a1 , R b1 And R d1 are the same or different -(CH 2 ) r -, r is an integer of 0-5; in one embodiment of the invention, R a1 and R d1 are both -C 2 H 4 -, R b1 is -C 3 H 6 -.
  • the -R b1 -B is -C 3 H 6 -OH.
  • the dendritic polyglycol derivative has the following structure:
  • R a1 , R b1 , R d1 , A 1 , A 2 , D 1 , D 2 , B and Z have the above definitions of the invention
  • M1-4 is independently selected from an integer from 0-100, such as an integer from 0-20, particularly an integer from 0 to 12; in one embodiment of the invention, the m1-6 is 4.
  • the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 CH One of 2 CH 2 CHO; in one embodiment of the invention, the B is -H.
  • the dendritic polyglycol derivative has the following structure:
  • M1-6 is independently selected from an integer from 0 to 100, such as an integer from 0 to 20, particularly an integer from 0 to 12; in one embodiment of the invention, the m1-6 is 3.
  • the X is selected from -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 a combination of one or more of i NH- and (CH 2 ) i CONH-, more specifically -(CH 2 ) i -; in particular, i in the linking group X is 0, 1, 2 3 or 4;
  • the X is a single bond, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a decyl group, a carboxyl group, an ester group, and an aldehyde.
  • a group, an acryl group, and a maleimide group is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a decyl group, a carboxyl group, an ester group, and an aldehyde.
  • the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and -CH One of 2 CH 2 CH 2 CHO; more specifically, the A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, One of -CH 2 CH 2 COOH and -CH 2 CH 2 N 3 ; in one embodiment of the invention, the A 1 , A 2 , D 1 and D 2 are both -CH 3 or -CH 2 CH 2 NH 2 ;
  • the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 CH One of 2 CH 2 CHO, further specifically -H or -CH 2 CH 2 COOH.
  • the R a1 , R b1 and R d1 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more specifically, the R a1 , R b1 And R d1 are the same or different -(CH 2 ) r -, r is an integer of 0-5; in one embodiment of the invention, R a1 and R d1 are both -C 2 H 4 -,R B1 is a single bond.
  • the Z is O or NHCO.
  • the -ZR b1 -B is -OH or -NHCO-CH 2 CH 2 COOH.
  • the dendritic polyglycol derivative has the following structure:
  • the invention also provides a preparation method of the above dendritic polyglycol derivative, which adopts a convergent synthesis method, comprising the following steps: (1) modifying one end of the polyglycol derivative to form a pro-center with the central molecule a nuclear substitution reaction or an amidation reaction to obtain a wedge-shaped structure;
  • a dendritic polyglycol derivative such as an eight-armed or sixteen-armed arm with an exponential increase in the number of arms can be obtained;
  • the polyglycol derivative described in the step (1) which has the structure RXER t -OH, RXER t -NH 2 or RXER t -COOH;
  • R t is selected from: -(CH 2 ) t -, -(CR 1 R 2 ) t -, -(CH 2 ) t NH-, -NHCO(CH 2 ) t -, -(CH 2 ) t CONH- and a combination of one or more of -CO(CH 2 ) t -, t is an integer from 0 to 30;
  • R 1 and R 2 are independently selected from: -H, C1-C6 alkyl, -OR', -NHR', -N(R') 2 , -CN, -F, -Cl, -Br, -I a combination of one or more of -COR', -COOR', -OCOR', -CONHR', and -CON(R') 2 ,
  • R is a living end group defined by Y in the structure of the formula (I) of the present invention or R is selected from the group consisting of a methyl ester, an ethyl ester, a tert-butyl ester, an acetal group, a benzyloxy group, a t-butoxy group, One of an imido group and a halogen;
  • the modifying group is selected from the group consisting of: (-OTs), (-OMs), (-OBs),
  • p is an integer from 0 to 10;
  • V is O or NH.
  • the X is selected from a combination of one or more of -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 ) i NH-, and (CH 2 ) i CONH-, It is preferably -(CH 2 ) i -.
  • the R is selected from the group consisting of methyl ester, ethyl ester, tert-butyl ester, azido group, acetal group, and benzyloxy group.
  • the m is an integer of 0-20, such as an integer of 0-12; more specifically, the m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  • the p is 0, 1, 2, 3, 4 or 5.
  • the central molecule contains the structure: -NH 2 ,
  • one end of the central molecular moiety in the reaction product obtained in the step (1) and/or the step (2) may be bonded to the leaving group-modified polyglycol glycol by an affinity substitution reaction.
  • the step of modifying the ionic group in the above preparation method and the step of nucleophilic substitution reaction with the central molecule can be carried out by the method disclosed in the prior art, which is not specifically limited in the present invention.
  • the use is the use of the dendritic polyethylene glycol derivative described above in biomedical applications.
  • the application is the use of the above dendritic polyglycol derivative in a modified drug; more specifically, the drug is a poorly soluble drug.
  • the present invention also provides a covalent conjugate comprising the above dendritic polyglycol derivative and a drug molecule linked by a covalent bond.
  • the drug is a poorly soluble drug.
  • the drug is cholesterol, cetyl alcohol or menthol.
  • the poorly soluble drug described in the present invention is a drug which is slightly soluble, slightly soluble, and extremely slightly soluble according to the detection method of the Chinese Pharmacopoeia.
  • the dendritic polyglycol derivative provided by the invention has a plurality of terminal functional groups, and has stronger water solubility than linear polyglycol glycol, and can solve the problem of polyglycol modified insoluble drugs.
  • the preparation method of the above-mentioned dendritic polyglycol glycol derivative provided by the invention has mild reaction conditions, is environmentally friendly, has low cost, and is easy to realize industrialization.
  • Figure 1 shows the synthetic route of (mEG 3 ) 2 NC 3 H 6 -OH(1).
  • Figure 4 shows the synthetic route of (N 3 -EG 4 ) 2 -EG 4 -OH(3).
  • Figure 5 is a synthetic route diagram of a dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH.
  • Figure 7 shows the synthetic route of the dendrimer ((mEG 3 ) 2 -EG 4 ) 2 -OH.
  • alkoxy refers to a substituent formed by the substitution of a hydrogen in a hydroxy group by an alkyl group, and a C1-C6 alkoxy group means a 1-6 carbon atom.
  • TEA 1.6 g
  • 60 mL of DCM were placed in the reaction product of the above step (7.5 g), and placed in a reaction flask in an ice water bath.
  • MsCl (1.76 g) was dissolved in DCM (15 mL), dissolved, and then taken to a reaction flask in an ice water bath.
  • the reaction was carried out for 3 hours at room temperature. Wash it with water.
  • the organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. Concentration gave the product about 8.1 g (yield 95%).

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Abstract

La présente invention concerne un dérivé de polyglycol dendritique, son procédé de préparation et son application. Le dérivé de polyglycol dendritique est représenté par la structure de formule (I), présente une pluralité de groupes fonctionnels terminaux, et une meilleure hydrosolubilité par comparaison avec des polyglycols à chaîne droite. Le dérivé de polyglycol dendritique peut résoudre le problème d'une hydrosolubilité insuffisante provoquée par une augmentation de la charge lorsque les polyglycols sont utilisés pour modifier des médicaments insolubles. L'invention concerne également un procédé de préparation du dérivé de polyglycol dendritique. Ledit procédé a lieu dans des conditions de réaction modérées, est respectueux de l'environnement, présente de faibles coûts et est facile à mettre à l'échelle industrielle.
PCT/CN2018/093134 2017-06-28 2018-06-27 Dérivé de polyglycol dendritique, son procédé de préparation et son application WO2019001473A1 (fr)

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CN201711241222.2 2017-11-30
CN201711241222.2A CN109134282B (zh) 2017-06-28 2017-11-30 一种树状多缩乙二醇衍生物及其制备方法和应用

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101389354A (zh) * 2005-11-30 2009-03-18 遗传工程与生物技术中心 用于与蛋白质和肽缀合的四个支链的树枝状大分子peg
CN102367291A (zh) * 2011-04-26 2012-03-07 刘超 含单官能团的多级支化聚乙二醇及其合成方法
CN104387577A (zh) * 2013-05-28 2015-03-04 厦门赛诺邦格生物科技有限公司 一种具有氮原子支化中心的单一官能化聚乙二醇、制备方法及其生物相关物质
CN106146325A (zh) * 2015-04-24 2016-11-23 北京键凯科技有限公司 一种y型多缩乙二醇衍生物及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101389354A (zh) * 2005-11-30 2009-03-18 遗传工程与生物技术中心 用于与蛋白质和肽缀合的四个支链的树枝状大分子peg
CN102367291A (zh) * 2011-04-26 2012-03-07 刘超 含单官能团的多级支化聚乙二醇及其合成方法
CN104387577A (zh) * 2013-05-28 2015-03-04 厦门赛诺邦格生物科技有限公司 一种具有氮原子支化中心的单一官能化聚乙二醇、制备方法及其生物相关物质
CN106146325A (zh) * 2015-04-24 2016-11-23 北京键凯科技有限公司 一种y型多缩乙二醇衍生物及其制备方法

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