CN103641925A - Covalent polycompound of water-soluble polysaccharide and taxane compound, and preparation method and medical application of covalent polycompound - Google Patents
Covalent polycompound of water-soluble polysaccharide and taxane compound, and preparation method and medical application of covalent polycompound Download PDFInfo
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Abstract
The invention relates to a covalent polycompound of water-soluble polysaccharide and taxane, and a preparation method and medical application of the covalent polycompound. The method disclosed by the invention comprises the following step: connecting the taxane compound to the water-soluble polysaccharide through a covalent bond by adopting selective protection and selective deprotection methods and a plurality of degradable structure units, so as to obtain the covalent polycompound which can retain the biological activity of the taxane compound and is relatively simplex in structure. The novel covalent polycompound is good in water solubility, and can replace an existing clinical taxane preparation free of a cosolvent with toxic and side effects.
Description
Technical field
The present invention relates to the water-soluble saccharan Taxan of a class copolymerization, its preparation method and medicinal use thereof.The invention still further relates to the midbody compound of water-soluble saccharan Taxan, described compound or copolymerization have anti-tumor activity.
Background technology
Clinical use taxanes carcinostatic agent comprises taxol (Paclitaxel, Taxol) and Docetaxel (having another name called docetaxel, Docetaxel, Docetere).
This compounds is tubulin stablizer, has remarkable antitumour activity, in more than 40 countries, gets permission listing, as the curative of the diseases such as vascular restenosis of ovarian cancer, mammary cancer, lung cancer, leukemia, gastrointestinal cancer and PTCA or and STENTS.Yet taxanes is treated agent poorly water-soluble, his the match rule agent of the taxol of clinical use and polyenoid need to be added solubility promoter as Cremophor EL (containing polyoxyethylenated castor oil), tween-80.But Cremophor EL can cause the serious adverse reactions such as serious anaphylaxis and renal toxicity and neurotoxicity.And tween-80 can cause serious allergy and cause the immunity system toxicity such as neutrophilic granulocytopenia, caused great infringement [Chin.J.New Drugs Clin.Rem.2010:29 (10), 721-728] to patient's body and mind.
In order to remove the side effect of solubility promoter from, development in recent years prodrug, emulsion, micella, inclusion compound, liposome, nanoparticle, gel, implant and drug releasing stent etc., particularly taxol drug releasing bracket (TAXUS
tM) and albumin nano granular injection liquid (Abraxane) in succession by FDA approval listing [Chin.Pharm.J.2006:41 (18), 1366-1370].In these compounds and preparation, the prodrug that has a class to have applications well prospect is the multipolymer that taxol is combined with water-soluble saccharan, its water-soluble and homogeneity is all better than emulsion, micella, inclusion compound, liposome, nanoparticle, gel, implant and drug releasing stent, and there is no protein, the intrinsic immunogenicity of antibody and polypeptide itself.Shu-ichi Sugahara report, by ehter bond by dextran carboxymethylation, then with covalent linkage be connected with taxol [Journal of Controlled Release2007:117,40 – 50].Due to the ehter bond forming after carboxymethylation be difficult to degraded by enzymes, thereby approximation surface promoting agent carboxymethyl cellulose (CMC) structurally after dextran carboxymethylation, its security needs further to investigate.The reports such as Junichi Nakamura, are used coupling agent N, and N'-carbonyl dimidazoles is two primary amine syndetons unit be connected with taxol covalency with dextran [Anticancer Research2010:30,903-910] freely.But this method has two shortcomings in actual applications: the one, and primary amine, can slough the benzoyl on paclitaxel lateral chain freely; The 2nd, yield is low.Separately have bibliographical information, the covalency body of taxol and polysaccharide is used for developing target and treats agent.Antonio Rosato report waits taxol by ester bond be connected with hyaluronic acid [Urologic Oncology:Seminars and Original Investigations2006:24,207 – 215].Yet this preparation method, the cycle is long and yield is low.The report such as Francesca Leonelli is connected taxol [Molecules2008,13,360-378] by hydrazides with hyaluronic acid., after this multipolymer degradation in vivo, can discharge the hydrazine that has hepatotoxicity, thereby security is bad.
In addition, the saccharan taxol multipolymer of above-mentioned all reports has a common shortcoming, and in fact they be not the multipolymer that structure is single, and problem is not solve covalently bound structural unit regioselectivity problem.On taxol, there are three alcoholic extract hydroxyl groups freely, are distributed in 1,7 and 2 ' position.Taxol 1-position hydroxyl torpescence, does not participate in reaction conventionally.Although 7-position hydroxyl reaction is active in 2 ' position hydroxyl, at coupling agent as carbodiimide class (DCC, EDC, DIPC etc.), N, under N'-carbonyl dimidazoles etc. act on, 7-position hydroxyl still reacts with carboxyl, acid anhydrides and free primary amine or secondary amine.And substituting group is connected on the alcoholic extract hydroxyl group of 7-position, can greatly reduce the antitumour activity of bearing taxanes.
Although the antitumour activity of Docetaxel, than 2～5 times of taxols, has no the covalent polymer of bibliographical information saccharan and Docetaxel.Reason is that Docetaxel has 4 alcoholic extract hydroxyl groups freely, and 7,10 and 2 ' position alcoholic extract hydroxyl group wherein all can participate in chemical reaction, thereby the covalency body difficulty of the preparation single Docetaxel of structure and saccharan is larger.
Summary of the invention
The present invention adopts selective protection bearing taxanes hydroxyl and selectivity Deprotection, and paclitaxel analog compound is connected on water-soluble saccharan by covalent linkage, obtains structure relatively single, good water solubility, and can keep bioactive covalent polymer.Under the effect of animal plasma enzyme, saccharan Taxan covalent polymer can discharge bearing taxanes or their derivative.
The invention provides the water-soluble saccharan Taxan of a kind of general formula (I) covalent polymer, or its pharmacy acceptable salt or solvate,
Wherein water-soluble saccharan is selected from homopolysaccharide or mixed polysaccharide, (as the cyclodextrin) that it is that be straight chain, side chain or annular; Described bearing taxanes is selected from take compound and the derivative thereof that Taxan diterpene is parent nucleus, as taxol (Taxol), Docetaxel (docetaxel, docetere) etc.
Described degradable structural unit can be straight chain, side chain or annular, is selected from and contains ester bond, amido linkage, isourea key, amino-formate bond, amino bamic acid ester bond, thiocarbamide key, urea key, disulfide linkage, carbonic acid ester bond, phosphoric acid ester bond; Or containing triazole and the derivative condensed ring fragment of triazole [as 1,6a-pyrrolin [3,4-d] triazole-4 also, 6(5aH, 5H)-diketone], 2-alkyl sulphur succinic acid lactan; Or containing the structure fragment of aryl, heteroaryl or fatty group etc.
Preferably, described water-soluble saccharan is selected from the polysaccharide of vegetable polysaccharides, animal polysaccharide, microbial polysaccharide or synthetic.
More preferably, the sugar unit of described homopolysaccharide is selected from five-carbon sugar, hexose, seven carbon sugar, eight carbon sugar etc., for example dextran, xylan.The sugar unit of described mixed polysaccharide is mixed and is formed by above-mentioned homopolysaccharide unit, preferably transparent matter acid etc.
Also more preferably, the glycosidic bond between the sugar unit of described homopolysaccharide or mixed polysaccharide can be α type (as water soluble starch), or β type (as water soluble cellulose), or α, β mixed type.
Further preferably, the sugar unit of described water-soluble saccharan, is selected from the substituent sugar unit of Rb (as hydroxyethylamyle), natural desoxy sugar unit (as rhamnosyl), aminosugar unit (as galn, sialic acid, chitosan) etc.Wherein Rb is selected from ethanoyl (as chitin), carboxylic acid group, carboxylic acid sodium base, sulfonic group, sodium sulfonate group, hydroxyethyl, methyl, acyl group or hydroxypropyl etc.
Still more preferably, described water-soluble saccharan is hyaluronic acid, xylan, water soluble starch, hydroxyethylamyle, water soluble cellulose, galn, sialic acid, rhamnosyl, left-handed glucosides, dextran.Most preferably be dextran, hyaluronic acid, hydroxyethylamyle, ganoderan.
2. Taxan covalent polymer according to claim 1, is characterized in that, the general formula of described degradable structural unit is as shown in the table:
Table 1. degradable structural unit general formula
In said structure general formula, optional water-soluble saccharan or the Taxan of connecting of left end or right-hand member.
Wherein, Y
1be selected from O, S, NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl); Y
2be selected from O, NH or S; Y
3be selected from O or NR (R is H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl); The integer of n=0-10;
Z
1, Z
2, Z
3, Z
4, Z
5, Z
6be selected from straight-chain alkyl, branched hydrocarbyl, containing heteroatomic straight-chain alkyl, containing heteroatomic branched hydrocarbyl, unsaturated straight-chain alkyl, unsaturated side chain alkyl, containing heteroatomic unsaturated straight-chain alkyl, containing heteroatomic unsaturated side chain alkyl, saturated cyclic, unsaturated cyclic hydrocarbon radical, containing heteroatomic cyclic hydrocarbon radical, containing heteroatomic unsaturated cyclic hydrocarbon radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl etc.Described Z
1, Z
2, Z
3, Z
4, Z
5, Z
6optionally by Ra, replaced;
X
1, X
2, X
3, X
4, X
5, X
6be selected from independently of one another amino acid and (comprise D and L-type amino acid, the amino acid of natural amino acid and synthetic; Also comprise α, beta, gamma, δ, and epsilon-amino acid; β-alanine for example, γ-aminobutyric acid or epsilon-amino caproic acid) or amino acid whose N-hydrocarbylation derivative;
L
1, L
2, L
3be selected from independently of one another O, NH, S, straight-chain alkyl, branched hydrocarbyl, containing heteroatomic straight-chain alkyl, containing heteroatomic branched hydrocarbyl, unsaturated straight-chain alkyl, containing heteroatomic unsaturated straight-chain alkyl, saturated cyclic, unsaturated cyclic hydrocarbon radical, containing heteroatomic saturated cyclic, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, shorter polymer segments (the polyoxyethylene glycol (PEG) that for example molecular weight is 100～20000, polymeric amide, PLGA (PLGA)) etc.L
1, L
2, L
3optionally by Ra, replaced; Ra is selected from hydrogen, halogen, C
1-6alkoxyl group, C
1-6alkyl, cyano group, amino, nitro, C
1-6alkylamino or two (C
1-6alkyl) amino.
According to the present invention, described R ' is selected from H, C1-6 alkyl, halo C1-6 alkyl; Hydroxyl C1-6 alkyl, C1-6 alkyloyl.
According to the present invention, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6be selected from independently of one another straight or branched C
1-10alkyl (preferred C
1-8alkyl, more preferably C
1-6alkyl); Containing heteroatomic straight or branched C
1-10alkyl (preferred C
1-8alkyl, more preferably C
1-6alkyl); Straight or branched C
2-10thiazolinyl (preferred C
2-8thiazolinyl, more preferably C
2-6thiazolinyl); Containing heteroatomic straight or branched C
2-10thiazolinyl (preferred C
2-8thiazolinyl, more preferably C
2-6thiazolinyl); Straight or branched C
2-10alkynyl (preferred C
2-8alkynyl, more preferably C
2-6alkynyl), containing heteroatomic cyclic hydrocarbon radical straight or branched C
2-10alkynyl (preferred C
2-8alkynyl, more preferably C
2-6alkynyl), C
3-10cycloalkyl (C more preferably
3-8cycloalkyl, also C more preferably
3-6cycloalkyl), C
3-10cycloalkenyl group (preferred C
3-8cycloalkenyl group, more preferably C
3-6cycloalkenyl group), containing at least one, be selected from N, the heteroatomic 3-10 of O or S unit Heterocyclylalkyl (more preferably 3-6 unit Heterocyclylalkyl), is selected from N containing at least one, the heteroatomic 3-10 of O or S unit heterocycloalkenyl (more preferably 3-6 unit heterocycloalkenyl), aryl; Heteroaryl; Aryl C
1-10alkyl or heteroaryl C
1-10alkyl.
X
1, X
2, X
3, X
4, X
5, X
6be selected from independently of one another natural amino acid, the derivative of alpha-non-natural amino acid (as D-type amino acid, β-alanine, γ-aminobutyric acid or epsilon-amino caproic acid etc.) or their N-hydrocarbylation.
L
1, L
2, L
3be selected from independently of one another O, NH, S, straight or branched C
1-10alkyl (preferred C
1-8alkyl, more preferably C
1-6alkyl); Containing heteroatomic straight or branched C
1-10alkyl (preferred C
1-8alkyl, more preferably C
1-6alkyl); Straight or branched C
2-10thiazolinyl (preferred C
2-8thiazolinyl, more preferably C
2-6thiazolinyl); Containing heteroatomic straight or branched C
2-10thiazolinyl (preferred C
2-8thiazolinyl, more preferably C
2-6thiazolinyl); Straight or branched C
2-10alkynyl (preferred C
2-8alkynyl, more preferably C
2-6alkynyl), containing heteroatomic cyclic hydrocarbon radical straight or branched C
2-10alkynyl (preferred C
2-8alkynyl, more preferably C
2-6alkynyl), C
3-10cycloalkyl (C more preferably
3-8cycloalkyl, also C more preferably
3-6cycloalkyl), C
3-10cycloalkenyl group (preferred C
3-8cycloalkenyl group, more preferably C
3-6cycloalkenyl group), containing at least one, be selected from N, the heteroatomic 3-10 of O or S unit Heterocyclylalkyl (more preferably 3-6 unit Heterocyclylalkyl), is selected from N containing at least one, the heteroatomic 3-10 of O or S unit heterocycloalkenyl (more preferably 3-6 unit heterocycloalkenyl), aryl; Heteroaryl; Aryl C
1-10alkyl or heteroaryl C
1-10alkyl; Aryl C
2-10thiazolinyl or heteroaryl C
2-10thiazolinyl; Or the fragment of shorter polymkeric substance be 100～20000 as molecular weight polyoxyethylene glycol (PEG), polymeric amide, PLGA (PLGA) etc.
According to the present invention, described degradable structural unit is selected from:
According to the present invention, 2 of described taxol or Docetaxel ' position, 7 or 10 are connected with degradable structural unit, and preferably 2 ' position or 7 are connected with degradable structural unit, more preferably 2 ' be connected with degradable structural unit.
According to the present invention, described degradable structural unit can be following structure: covalent linkage or structure fragment-spacer (1) that-spacer-formation connects; Covalent linkage or structure fragment-spacer-(2) that-formation connects.Preferably, the spacer in formula (1) can be connected with bearing taxanes or be connected with water-soluble saccharan; In formula (2), spacer is connected with bearing taxanes, forms the covalent linkage or the structure fragment that connect and is connected with water-soluble saccharan.Preferably, wherein said spacer is to be all connected with bearing taxanes or water-soluble saccharan with covalent linkage.From Taxan, or/and the direct or indirect and corresponding functional group of the functional group of water-soluble saccharan reacts, form covalent linkage or the structure fragment connecting, thereby bearing taxanes is connected on water-soluble saccharan.
According to the present invention, described covalent polymer preferably has following structure:
Wherein: R
1be selected from H or ethanoyl, R
2be selected from tert-butoxycarbonyl or benzoyl; Preferred R
1be selected from H, R
2be selected from tert-butoxycarbonyl; Or R
1be selected from ethanoyl, R
2be selected from benzoyl.
Described spacer is straight chain, side chain, the structure of annular, is selected from and contains for example [CH of heteroatomic straight-chain alkyl
2oCH
2]
1-20, [CH
2sCH
2]
1-20deng, or 1-20 amino acid forms little peptide fragment, or shorter polymer segments, if molecular weight is 100～20,000 polyoxyethylene glycol (PEG), polymeric amide, PLGA (PLGA) etc.; Or the fragment of amide bond, ester bond, substituted-amino; Or containing the structure fragment of aryl, heteroaryl or fatty group.
The covalent linkage that described formation connects is selected from ester bond, amido linkage, isourea key, amino-formate bond, amino bamic acid ester bond, thiocarbamide key, urea key, disulfide linkage, carbonic acid ester bond, phosphoric acid ester bond, sulphonamide key.
The structure fragment of described connection is straight chain, side chain or annular, is selected from and contains ester bond, amido linkage, isourea key, urea key, amino-formate bond, amino bamic acid ester bond, thiocarbamide key, disulfide linkage, carbonic acid ester bond, phosphoric acid ester bond; Or containing triazole and the derivative condensed ring fragment of triazole [as 1,6a-pyrrolin [3,4-d] triazole-4 also, 6(5aH, 5H)-diketone], 2-alkyl sulphur succinic acid lactan fragment; Or containing the structure fragment of aryl, heteroaryl or fatty group.
Described water-soluble saccharan as previously mentioned.
According to the present invention, described covalent polymer is selected from the covalent polymer of following structure:
The present invention also provides the Taxane derivative that contains functional group with degradable structural unit of a kind of general formula (II):
R wherein
4be selected from benzoyl or tertiary fourth oxygen acyl group (BOC);
R
1, R
2and R
3be selected from independently of one another:
(1) H, ethanoyl, allyloxycarbonyl, benzyl oxygen carbonyl, tertiary butyl dimethylsilyl, triethyl silyl, TMS;
(2) be selected from following formula III-1, III-2, III-3, III-4, the substituting group containing 1,2,3-triazole of III-5 or III-6;
Formula III-1, III-2, III-3, III-4, in III-5 or III-6, n is identical or different separately, is selected from the integer of 0-20.
X
1, X
2be selected from independently of one another O, S, NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl) or straight-chain alkyl, for example (CH
2)
1-20; Or for example, containing heteroatomic straight-chain alkyl, [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20;
Ar is that aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, shorter polymer segments are as [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20;
（3）
Wherein, the covalent linkage that connects Taxan described in is selected from ester bond, amino-formate bond, carbonic acid ester bond, thiocarbamate key, phosphoric acid ester bond, isourea key;
Described spacer is straight chain, side chain or annular, is for example selected from, containing heteroatomic straight-chain alkyl, [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20, 1-20 amino acid whose peptide fragment; Shorter polymer segments, for example molecular weight is 100～20,000 polyoxyethylene glycol (PEG), polymeric amide, PLGA (PLGA); Or the fragment of amide bond, ester bond, substituted-amino; Or containing the structure fragment of aryl, heteroaryl or fatty group.
X is functional group, is selected from azido-(N
3), the amino SR ' of alkynyl (C ≡ CH), amino, the amino HNR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl) replacing, sulfydryl, replacement (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl), carboxyl, fat base, amide group or protection amino and contain the fragment of toxilic acid lactan;
(4) as shown in the formula containing azido-(N shown in IV
3) or the amino SR ' of the amino substituting group of the amino HNR ' of acetylene bond, amino, replacement (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl), carboxyl, fat base, amide group or protection, sulfydryl, replacement and containing the fragment of toxilic acid lactan:
In formula, n is identical or different separately, is selected from the integer of 0-20;
X
1, X
2, X
3be selected from independently of one another O, NH, S, NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl) or straight-chain alkyl, for example (CH
2)
1-20; Or containing heteroatomic straight-chain alkyl; [CH for example
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20; In addition, X
1also be selected from dibasic cyclic hydrocarbon radical, dibasic containing heteroatomic ring alkyl, dibasic aromatic base or dibasic containing heteroatoms aromatic base;
X
a, X
b, X
c, X
d, X
e, X
f, X
g, X
h, X
i, X
jbe selected from independently of one another any one natural or non-natural amino acid;
Y
1, Y
2be selected from independently of one another O, S or NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl);
R is selected from independently of one another into H, allyl group, benzyl,, allyloxycarbonyl silica-based to methoxybenzyl, trialkyl, benzyl oxygen carbonyl and containing the fragment of toxilic acid lactan etc.;
T is selected from azido-(N independently of one another
3), the amino of amino, protection, sulfydryl, the sulfydryl of protection, the amino of replacement or alkynyl and containing the fragment of toxilic acid lactan;
Ar is selected from aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, shorter polymer segments as [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20;
(5) or containing aromatic base phosphine, or containing the substituting group of aromatic base phosphine boron trihydride mixture.
According to the present invention, X
1, X
2, X
3be selected from independently of one another O, S, NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl), straight or branched C
1-10alkyl (preferred C
1-8alkyl, more preferably C
1-6alkyl); Containing heteroatomic straight or branched C
1-10alkyl (preferred C
1-8alkyl, more preferably C
1-6alkyl);
Ar is selected from aryl, heteroaryl, aryl C
1-10alkyl or heteroaryl C
1-10alkyl, aryl C
2-10thiazolinyl or heteroaryl C
2-10the polyoxyethylene glycol (PEG) that thiazolinyl, molecular weight are 100～20000, polymeric amide, PLGA (PLGA).
According to the present invention, preferred R
2be selected from H, ethanoyl, allyloxycarbonyl, benzyl oxygen carbonyl, tertiary butyl dimethylsilyl; R
1and R
3be selected from independently of one another the definition of any one in above-mentioned (2)-(5).More preferably R
2and R
3be selected from independently of one another H, ethanoyl, allyloxycarbonyl, benzyl oxygen carbonyl, tertiary butyl dimethylsilyl; R
1be selected from the definition of any one in above-mentioned (2)-(5).More preferably R also
1and R
2be selected from independently of one another H, ethanoyl, allyloxycarbonyl, benzyl oxygen carbonyl, tertiary butyl dimethylsilyl; R
3be selected from the definition of any one in above-mentioned (2)-(5).
Preferably, described R
1, R
2, R
3be selected from independently of one another following structure:
Preferably, described Taxane derivative is selected from following structure:
The present invention also provides a kind of water-soluble saccharan with functional group, and it has the structure as shown in following general formula V
Wherein water-soluble saccharan is selected from homopolysaccharide or mixed polysaccharide, and it is (as cyclodextrin) straight chain, side chain or annular;
Described spacer be straight chain, side chain, annular, be for example selected from, containing heteroatomic straight-chain alkyl, [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20deng, the amino acid whose peptide fragment of 1-20, shorter polymer segments, if molecular weight is 100～20,000 polyoxyethylene glycol (PEG), polymeric amide, PLGA (PLGA) etc.; Or the fragment of amide bond, ester bond, substituted-amino; Or containing the structure fragment of aryl, heteroaryl or fatty group.
Described functional group is selected from azido-(N
3), alkynyl (C ≡ CH), thiazolinyl (CH=CH
2), the amino of carboxyl, ester group, sulfonic group, sulfydryl, amide group, amino, replacement (HNR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl) or protection amino and containing the fragment of toxilic acid lactan.
According to the present invention, described water-soluble saccharan is the polysaccharide of vegetable polysaccharides, animal polysaccharide, microbial polysaccharide or synthetic.
According to the present invention, the sugar unit of described homopolysaccharide is selected from five-carbon sugar, hexose, seven carbon sugar, eight carbon sugar etc., for example dextran, xylan.The sugar unit of described mixed polysaccharide is mixed and is formed by above-mentioned homopolysaccharide unit, preferably transparent matter acid etc.
According to the present invention, the glycosidic bond between the sugar unit of described homopolysaccharide or mixed polysaccharide can be α type (as water soluble starch), or β type (as water soluble cellulose), or α, β mixed type.
According to the present invention, the sugar unit of described water-soluble saccharan, is selected from the substituent sugar unit of Rb (as hydroxyethylamyle); Natural desoxy sugar unit (as rhamnosyl); Aminosugar unit (as galn, sialic acid), wherein Rb is selected from ethanoyl, carboxylic acid group, carboxylic acid sodium base, sulfonic group, sodium sulfonate group, hydroxyethyl, methyl, acyl group or hydroxypropyl.
According to the present invention, described water-soluble saccharan is preferably hyaluronic acid, xylan, water soluble starch, hydroxyethylamyle, water soluble cellulose, galn, sialic acid, rhamnosyl, left-handed glucosides, dextran, most preferably is dextran, hyaluronic acid, hydroxyethylamyle, ganoderan.
The molecular weight ranges of described water-soluble saccharan can be 300～3,000,000.
According to the present invention, described in connect polysaccharide covalent linkage be selected from ester bond, amido linkage, isourea key, urea key, amino-formate bond, amino bamic acid ester bond, thiocarbamide key, disulfide linkage, carbonic acid ester bond, phosphoric acid ester bond, sulphonamide key etc.
According to the present invention, the water-soluble saccharan of described functionalization, contains azido-(N
3), acetylene bond, amino, carboxyl, sulfydryl, isoureido, isothiocyano, sulfydryl, different oxygen cyano group and containing the fragment of toxilic acid lactan etc.
According to the present invention, the water-soluble polysaccharide of described functionalization preferably has following structure:
In formula, n is identical or different separately, is selected from 0-20, preferably 1-10, the more preferably integer of 2-6;
X
1, X
2be selected from independently of one another O, S, NR ' (R ' be the substituting group of H or an any type), straight-chain alkyl ((CH for example
2)
1-20; Or for example, containing heteroatomic straight-chain alkyl ([CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20) or with the substituent alkyl of Ra; Ra is selected from hydrogen, halogen, C
1-6alkoxyl group, C
1-6alkyl, cyano group, amino, nitro, C
1-6alkylamino or two (C
1-6alkyl) amino;
Y
1, Y
2, Y
3be selected from independently of one another O, S or NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl);
X
a, X
b, X
c, X
d, X
e, X
f, X
g, X
h, X
i, X
jcan be selected from independently of one another any one natural or non-natural amino acid;
Q substituting group is selected from H, carboxyl, azido-(N independently of one another
3), the amino of the amino or protection of alkynyl, amino, replacement, sulfydryl, isothiocyano, different oxygen cyano group and containing the fragment of toxilic acid lactan;
Ar is selected from aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, shorter polymer segments as [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20.
According to the present invention, described R ' is selected from H, C
1-6alkyl, halo C
1-6alkyl; Hydroxyl C
1-6alkyl, C
1-6alkyloyl.
According to the present invention, X
1, X
2be selected from independently of one another O, S, NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl), straight or branched C
1-10alkyl (preferred C
1-8alkyl, more preferably C
1-6alkyl), containing heteroatomic straight or branched C
1-10alkyl (preferred C
1-8alkyl, more preferably C
1-6alkyl).
According to the present invention, described in
be selected from following structure:
Preferably, the described water-soluble saccharan with functional group is selected from following structure:
According to the present invention, described alkyl is selected from alkyl, and described alkyl is straight or branched alkyl, for example C
1-10alkyl, preferred C
1-8alkyl, more preferably C
1-6alkyl, includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl etc.
According to the present invention, described unsaturated alkyl is selected from thiazolinyl and alkynyl.Described thiazolinyl is the thiazolinyl of straight or branched, for example C
2-10thiazolinyl, preferably C
2-8thiazolinyl, more preferably C
2-6thiazolinyl, includes but not limited to ethene, propylene, butylene, iso-butylene, amylene, isopentene, hexene etc.Described alkynyl is the alkynyl of straight or branched, for example C
2-10alkynyl, preferably C
2-8alkynyl, more preferably C
2-6alkynyl, includes but not limited to acetylene, propine, butine etc.
According to the present invention, described cyclic hydrocarbon radical can be saturated cyclic and unsaturated cyclic hydrocarbon radical.Described saturated cyclic is cycloalkyl, is preferably C
3-10cycloalkyl, more preferably C
3-8cycloalkyl, also C more preferably
3-6cycloalkyl, also more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.Described cycloalkyl is optionally by aforementioned substituting group, as alkyl, thiazolinyl, alkynyl, aryl or heteroaryl replace.
According to the present invention, described unsaturated alkyl can be cycloalkenyl group, and described cycloalkenyl group is C
3-10cycloalkenyl group, preferably C
3-8cycloalkenyl group, more preferably C
3-6cycloalkenyl group, also more preferably cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl.Described cycloalkenyl group is optionally replaced by aforementioned substituting group.
According to the present invention, described heteroatoms at least one, be preferably 1-4, described heteroatoms is preferably N, O, the heteroatomss such as S.
According to the present invention, described can be heterocycle containing heteroatomic saturated alkyl, be preferably 3-8 unit heterocycle, 3-6 unit heterocycle more preferably, for example tetrahydrofuran (THF), tetramethylene sulfide, azetidine, acridine, Pyrrolidine, 1,3-thiazoline, 1,3-dihydro-oxazole, piperidines, piperazine, morpholine, thiomorpholine, thiazine.Described heterocycle is optionally by H or C
1-6alkyl replaces, preferably by C
1-4alkyl replaces.
According to the present invention, described aryl is monocycle or Bicyclic alkyl, and described aryl is preferably phenyl, naphthyl, phenyl more preferably.Described aryl is optionally replaced by above-mentioned substituting group.
According to the present invention, heteroaryl is the assorted aryl radical of monocycle or dicyclo, wherein containing heteroatomic ring, be preferably 5 Yuans or 6 Yuans heteroaryls, it contains at least one, preferably have 1-4 N, S, the heteroatomic aromatic nucleus of O, described heteroaryl is preferably pyridyl, pyrimidyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, indyl, pyrryl, thienyl, furyl, benzofuryl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, furazan base, thiadiazolyl group, tetrazyl etc.Described heteroaryl is optionally replaced by above-mentioned substituting group.
According to the present invention, aryl alkyl can be aryl C
1-6alkyl, aryl wherein as defined above, aryl C
1-6alkyl is optionally substituted.Aryl C
1-6alkyl is preferably benzyl.
According to the present invention, heteroaryl alkyl can be heteroaryl C
1-6alkyl, heteroaryl wherein as defined above, heteroaryl C
1-6alkyl is optionally replaced by aforementioned substituting group.Heteroaryl C
1-6alkyl is preferably picolyl, thenyl, furfuryl.
According to the present invention, described shorter polymer segments refers to, comprising: [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20molecular weight is 100～20,000 polyoxyethylene glycol (PEG), polymeric amide, PLGA (PLGA) etc.
The invention provides the preparation method of a kind of formula (I) covalent polymer; it adopts the hydroxyl of selective protection bearing taxanes; and optionally slough the part protecting group on bearing taxanes; then paclitaxel analog compound is connected on water-soluble saccharan by degradable structural unit, obtains covalent polymer of the present invention.
Wherein each several part as defined above.
The present invention also provides a kind of preparation method of covalent polymer of the present invention, it is characterized in that, described method comprises the steps:
(1) with hydroxyl protection reagent, protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently, with 7 of hydroxyl protection reagent protection taxanes chemical combination or/and 10 alcoholic extract hydroxyl groups;
(3) optionally, slough the hydroxyl protection reagent in step (1); Spacer with functional group is connected on 2 ' position of bearing taxanes;
(4) optionally, de-7 or/and the protecting group on 10 alcoholic extract hydroxyl groups, obtain the Taxane derivative of functionalization;
(5) optionally, water miscible saccharan is connected with the spacer with functional group, (wherein to carry out the object of functionalization be in order to connect fat-soluble bearing taxanes to water-soluble saccharan to obtain the water miscible saccharan of functionalization;
(6) under the effect of catalyzer or coupling agent, the Taxane derivative of step (4) functionalization is reacted with the water-soluble saccharan that water-soluble saccharan or step (5) obtain functionalization, obtain covalent polymer of the present invention.
Preferably, described method comprises the steps:
(1) by the tertiary fourth of diformazan silica-based (TBS), protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently, with 7 of allyl oxygen carbonyl acyl group (ALOC) or benzyloxy carbonyl acyl group (Z) protection bearing taxanes or/and 10 alcoholic extract hydroxyl groups;
(3) it is silica-based that selectivity is sloughed the tertiary fourth of diformazan; Under the effect of coupling agent and organic bases, the spacer with functional group is connected on 2 ' position of bearing taxanes;
(4) selectivity de-7 or/and the allyl oxygen carbonyl acyl group (ALOC) on 10 or benzyloxy carbonyl acyl group (Z), obtain the Taxane derivative of functionalization;
(5) optionally, under the effect of coupling agent and organic bases, water miscible saccharan is connected with the spacer with functional group, obtains the water miscible saccharan of functionalization;
(6), under the effect of catalyzer or coupling agent, the Taxane derivative of the functionalization that step (4) is obtained reacts with the water-soluble saccharan of the functionalization that water miscible saccharan or step (5) obtain, and obtains covalent polymer of the present invention.
According to the present invention, described functional group, spacer, coupling agent are as aforementioned every definition.
According to the present invention, described coupling agent is selected from: carbodiimide class (DCC, EDC, DIPC etc.) or N, N'-carbonyl dimidazoles; Described organic bases is selected from: tertiary amines (triethylamine, Trimethylamine 99, diisopropylethylamine etc.) or dimethylamino pyridine (DMAP), 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) etc.
According to the present invention, described catalyzer is selected from: cuprous halide (cuprous chloride, cuprous iodide etc.), the I valency mantoquita that vitamin C sodium salt or gallic acid and copper sulfate produce etc.
The present invention also provides a kind of preparation method of covalent polymer of the present invention, it is characterized in that, described method comprises the steps:
(1) with hydroxyl protection reagent, protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently, will with the spacer of functional group, receive 7 of bearing taxanes or/and on 10 alcoholic extract hydroxyl groups;
(3) selectivity is sloughed the hydroxyl protection reagent in step (1), obtains the Taxane derivative of functionalization,
(4) optionally, water miscible saccharan is connected with the spacer with functional group, obtain functionalization water miscible saccharan (wherein water-soluble saccharan carry out the object of functionalization be in order to connect fat-soluble bearing taxanes);
(5), under the effect of catalyzer or coupling agent, the Taxane derivative of the functionalization that step (3) is obtained reacts with the water-soluble saccharan of the functionalization that water-soluble saccharan or step (4) obtain, and obtains covalent polymer of the present invention.
Reaction process 1
Preferably, being prepared as follows that described method is concrete stated described in flow process:
(1) with 2 of the tertiary fourth of diformazan silica-based (TBS) protection Docetaxel or taxol ' alcoholic extract hydroxyl group;
(2) subsequently,, under the effect of coupling agent and organic bases, will with the spacer of functional group, receive Docetaxel or taxol 7 or/and on 10 alcoholic extract hydroxyl groups;
(3) selectivity is sloughed TBS;
(4) optionally, under the effect of coupling agent and organic bases, water miscible saccharan is connected with the spacer with functional group, obtains the water miscible saccharan of functionalization;
(5), under the effect of coupling agent and organic bases, the Docetaxel of the functionalization that step (3) is obtained or taxol react with the water-soluble saccharan of the functionalization that water-soluble saccharan or step (4) obtain, and obtain covalent polymer of the present invention.
According to the present invention, described functional group, spacer, coupling agent is as aforementioned every definition.
According to the present invention, described coupling agent is selected from: carbodiimide class (DCC, EDC, DIPC etc.) or N, N'-carbonyl dimidazoles; Described organic bases is selected from: tertiary amines (triethylamine, Trimethylamine 99, diisopropylethylamine etc.) or dimethylamino pyridine (DMAP), 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU) etc.
According to the present invention, described catalyzer is selected from: cuprous halide (cuprous chloride, cuprous iodide etc.), the I valency mantoquita that vitamin C sodium salt or gallic acid and copper sulfate produce etc.
Preferably, being prepared as follows that described method is concrete stated described in flow process:
(1) with 2 of the tertiary fourth of diformazan silica-based (TBS) protection Docetaxel or taxol ' alcoholic extract hydroxyl group;
(2) subsequently, with allyl oxygen carbonyl acyl group (ALOC) or benzyloxy carbonyl acyl group (Z) protection Docetaxel or taxol 7 or/and 10 alcoholic extract hydroxyl groups;
(3) selectivity is sloughed TBS; Under the effect of coupling agent and organic bases, the spacer with functional group is connected on 2 ' position of Docetaxel or taxol;
(4) selectivity de-7 or/and the allyl oxygen carbonyl acyl group (ALOC) on 10 or benzyloxy carbonyl acyl group (Z), obtain Docetaxel or the taxol of functionalization;
(5) optionally, under the use of coupling agent and organic bases work, water miscible saccharan is connected with the spacer with functional group, obtains the water miscible saccharan of functionalization;
(6), under the effect of coupling agent and organic bases, the Docetaxel of the functionalization that step (4) is obtained or taxol react with the water-soluble saccharan of the functionalization that step (5) obtains, and obtain covalent polymer of the present invention.
According to the present invention, the group that the described spacer with functional group contains the functionalization corresponding with Taxane derivative, for example acid amides, carboxyl, amino, azido-, sulfydryl, toxilic acid lactam group, aromatic base phosphine, alcoholic extract hydroxyl group, phenolic hydroxyl group; And the azido-, the alkynyl that form triazole.
According to the present invention, the hydroxyl protection reagent described in the alcoholic extract hydroxyl group of 2 ' position is selected from: the tertiary fourth of diformazan silica-based (TBS), triisopropylsilyl (TIP), triethyl silica-based (TES), the trimethyl silicon based or tertiary fourth of phenylbenzene silica-based (TBDPS).
According to the present invention, 7 or/and the hydroxyl protection reagent described in 10 alcoholic extract hydroxyl groups be selected from: allyloxycarbonyl (Aloc), benzyl oxygen carbonyl (Z), the silica-based (R of trialkyl
3si) etc.
Wherein functionalization group contains the functional group that can form covalent linkage, as carboxyl, amino, hydroxyl, and diazo, alkynyl, sulfydryl or containing toxilic acid lactan, aromatic base phosphine.
The present invention also provides the preparation method of Taxane derivative of the functionalization of a kind of general formula (II),
The present invention also provides a kind of preparation method of covalent polymer of the present invention, it is characterized in that, described method comprises the steps:
(1) with hydroxyl protection reagent, protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently, with 7 of hydroxyl protection reagent protection taxanes chemical combination or/and 10 alcoholic extract hydroxyl groups;
(3) optionally, slough the hydroxyl protection reagent in step (1); Spacer with functional group is connected on 2 ' position of bearing taxanes;
(4) optionally, de-7 or/and the protecting group on 10 alcoholic extract hydroxyl groups, obtain the Taxane derivative of functionalization;
Preferably, described method comprises the steps:
(1) by the tertiary fourth of diformazan silica-based (TBS), protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently, with 7 of allyl oxygen carbonyl acyl group (ALOC) or benzyloxy carbonyl acyl group (Z) protection bearing taxanes or/and 10 alcoholic extract hydroxyl groups;
(3) it is silica-based that selectivity is sloughed the tertiary fourth of diformazan; Under the effect of coupling agent and organic bases, the spacer with functional group is connected on 2 ' position of bearing taxanes;
(4) selectivity de-7 or/and the allyl oxygen carbonyl acyl group (ALOC) on 10 or benzyloxy carbonyl acyl group (Z), obtain the Taxane derivative of functionalization;
More preferably, being prepared as follows that described method is concrete stated described in flow process:
(1) with 2 of the tertiary fourth of diformazan silica-based (TBS) protection Docetaxel or taxol ' alcoholic extract hydroxyl group;
(2) subsequently, with allyl oxygen carbonyl acyl group (ALOC) or benzyloxy carbonyl acyl group (Z) protection Docetaxel or taxol 7 or/and 10 alcoholic extract hydroxyl groups;
(3) selectivity is sloughed TBS; Under the effect of coupling agent and organic bases, the spacer with functional group is connected on 2 ' position of Docetaxel or taxol;
(4) selectivity de-7 or/and the allyl oxygen carbonyl acyl group (ALOC) on 10 or benzyloxy carbonyl acyl group (Z), obtain Docetaxel or the taxol of functionalization;
According to the present invention, described coupling agent and organic bases are as aforementioned every definition
The present invention also provides the preparation method of Taxane derivative of the functionalization of general formula (II), it is characterized in that, described method comprises the steps:
(1) with hydroxyl protection reagent, protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently,, under the effect of coupling agent and organic bases, will with the spacer of functional group, receive 7 of bearing taxanes or/and on 10 alcoholic extract hydroxyl groups;
(3) selectivity is sloughed the hydroxyl protection reagent in step (1), obtains the Taxane derivative of functionalization.
Preferably, described method comprises the steps:
(1) by the tertiary fourth of diformazan silica-based (TBS), protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently,, under the effect of coupling agent and organic bases, will with the spacer of functional group, receive 7 of taxanes chemical combination or/and on 10 alcoholic extract hydroxyl groups;
(3) selectivity is sloughed the tertiary fourth of protecting group diformazan silica-based (TBS) of 2 ' position alcoholic extract hydroxyl group, obtains the Taxane derivative of functionalization,
More preferably, being prepared as follows that described method is concrete stated described in flow process:
(1) with 2 of the tertiary fourth of diformazan silica-based (TBS) protection Docetaxel or taxol ' alcoholic extract hydroxyl group;
(2) subsequently, will with the spacer of functional group, receive Docetaxel or taxol 7 or/and on 10 alcoholic extract hydroxyl groups;
(3) selectivity is sloughed TBS, obtains the Taxane derivative of functionalization.
According to the present invention, described functional group, spacer, coupling agent, organic bases are as aforementioned every definition.
In addition, the present invention also provides a kind of preparation method of the water miscible saccharan of functionalization of logical formula V, it is characterized in that, water miscible saccharan is connected with the spacer with functional group, obtains the water miscible saccharan of functionalization.
Particularly, comprise following method:
Method 1: by anhydrous saccharan and N, N'-carbonyl dimidazoles is dissolved in anhydrous DMSO, is heated to 30-70 ℃, the organic amine that then adds organic bases and contain functionalization, obtains functionalization saccharan.
Method 2: the saccharan that contains free carboxy (or amino) is dissolved in to anhydrous DMSO, reacts with the organic amine that contains functionalization (or carboxylic acid) under the effect of coupling agent and organic alkali catalyst, obtain functionalization saccharan.
Method 3: the carboxylic acid that contains functionalization and N, N'-carbonyl dimidazoles is dissolved in anhydrous DMSO, then adds organic bases to react with anhydrous saccharan, obtains functionalization saccharan.
Method 4: saccharan is water-soluble, then add cyanogen bromide and mineral alkali and aminocarboxylic acid, obtain functionalization saccharan.
According to the present invention, described functional group, coupling agent, organic bases are as aforementioned every definition.Mineral alkali is selected from sodium hydroxide, hydroxide Potassium, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus etc.
This class final product prepared by the present invention, existing well water-soluble, can, under the effect of animal plasma enzyme, discharge bioactive compound (seeing Fig. 1) again.
The present invention also provides a kind of pharmaceutical composition, and it comprises aforesaid formula of the present invention (I) covalent polymer, formula (II) or formula (III) compound or its pharmacy acceptable salt, and pharmaceutically acceptable conventional medicine vehicle or assistant agent.According to the present invention, described pharmaceutical composition contains formula of the present invention (II) or formula (III) compound or formula (I) covalent polymer of 0.1-95% weight conventionally.
The covalent polymer of formula of the present invention (II) or formula (III) compound or formula (I) or the pharmaceutical composition that contains it can unit dosage form administrations, and route of administration can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc.
The covalent polymer of formula of the present invention (II) or formula (III) compound or formula (I) or the pharmaceutical composition that contains it, route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, abdominal cavity or rectum etc.
The invention still further relates to a kind of pharmaceutical preparation, its behaviour with medicament or animal medicament, it is characterized in that, described preparation comprises aforesaid formula of the present invention (I) covalent polymer, formula (II) or formula (III) compound or its pharmacy acceptable salt, and pharmaceutically acceptable conventional medicine vehicle or assistant agent.Pharmaceutical preparation can be liquid dosage form or solid dosage.Described liquid dosage form can be true solution, colloidal type, particulate formulations, mixed suspension form; Described solid dosage can be tablet, capsule, dripping pill, aerosol, pill, pulvis emulsion, granule, suppository, freeze-dried powder etc.
Pharmaceutical composition of the present invention can ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation or various particulate delivery system.
For the suitable pharmaceutical dosage form of the unit of making, can be widely used various carrier well known in the art.For example thinner and absorption agent, as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, urea, calcium carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent, as water.Glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, sodium alginate, agar powder, sodium bicarbonate and Sodium Citrate, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, ten sodium disulfonates, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, as sucrose, three stearic acid glyceryl ester, theobroma oil, hydrogenation wet goods; Absorption enhancer, as quaternary ammonium salt etc.; Lubricant, as talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.For example the compounds of this invention or covalent polymer are made to injection, as solution, suspension solution agent, emulsion, freeze-dried powder, this preparation can be moisture or non-water, can be containing acceptable carrier, thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent in one or more pharmacodynamics.Described thinner is selected from the Unimac 5680 alcohol of water, ethanol, polyoxyethylene glycol, ethoxylation, Solsperse 2000 of polyoxy, polyoxyethylene sorbitol stearic acid etc.
In addition, in order preparing etc., to ooze injection liquid, can in injection, to add appropriate sodium-chlor, glucose, dextran, glycerine etc.In addition, also can add conventional solubility promoter, buffer reagent, PH conditioning agent etc.As needs, also can in pharmaceutical preparation, add tinting material, correctives or other materials.
For reaching the object that strengthens result for the treatment of, pharmaceutical composition of the present invention can be with any known medication administration.The dosage of pharmaceutical composition of the present invention depends on many factors, for example required prevention or the treatment character of disease and serious degree, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, therapeutic purpose, therefore the dosage of the compounds of this invention or covalent polymer can have variation in a big way, for example, can be 0.1 – 1000mg/kg body weight.Each treats that required total dose can be divided into repeatedly or by dose administration.In addition, in pharmaceutical composition of the present invention, can also contain other treatment medicine, dosage is used and adjusts in described compound or covalent polymer and the merging of other treatment medicine.
The present invention also provides the application of a kind of water-soluble saccharan in preparing antitumor drug.Preferably, for the preparation of the medicine of formula (I) covalent polymer.
Preferably, by water-soluble saccharan with also medicine or bioactive material beyond Taxan can be connected on water miscible saccharan, for increasing water-soluble and improve curative effect of medication.Mammary cancer, lung cancer, oral carcinoma, liver cancer, intestinal cancer, cancer of the stomach, blood cancer, bladder cancer, carcinoma of the pancreas, uterus carcinoma, skin carcinoma.More preferably, the dosage of described compound is the therapeutic dose that is equivalent to taxol or docetaxel.
The application of the Taxane derivative that the present invention also provides a kind of formula (I) covalent polymer or formula (II) in preparing antitumor drug.
According to the present invention, preferably, described tumour comprises mammary cancer, lung cancer, oral carcinoma, liver cancer, intestinal cancer, cancer of the stomach, blood cancer, bladder cancer, carcinoma of the pancreas, uterus carcinoma, skin carcinoma etc.Their dosage is the therapeutic dose that is equivalent to taxol or docetaxel.0.5～500 mg/kg, preferably 5～500 mgs/kg, more preferably 10～300 mgs/kg, more preferably 20-200 mg/kg.
Accompanying drawing explanation
Fig. 1. drug release schematic diagram
Fig. 2. compound 67 and polysaccharide covalent polymer 69 discharge active taxol under rat plasma catalysis
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment can not be as limiting the scope of the invention, and any improvement of making on basis of the present invention is all without prejudice to spirit of the present invention.
Synthetic route 1.
Reaction conditions and reagent:
A) TERT-BUTYL DIMETHYL CHLORO SILANE/imidazoles, dimethyl formamide, room temperature, 24h;
B) two (trimethylsilyl) Lithamide/chloroformic acid benzyl ester, anhydrous tetrahydro furan ,-70 ℃, 1h;
C) tetrabutyl ammonium fluoride, tetrahydrofuran (THF), room temperature, 2h;
D) 6-nitrine n-hexyl-diglycollic acid monoesters/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
E) palladium-carbon/hydrogen, methyl alcohol, room temperature, 12h;
F) N, N'-carbonyl dimidazoles/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h.
Embodiment 1: compound 1 synthetic
In 250mL round-bottomed flask, add successively 9.32g (11.53mmol) Docetaxel, 2.20g (33.84mmol) imidazoles and 20mL solvent dimethylformamide, then add 5.21g (34.59mmol) TERT-BUTYL DIMETHYL CHLORO SILANE.At room temperature, stir 12 hours.React complete, reaction mixture distributes at saturated nacl aqueous solution (250mL) and ethyl acetate (250mL), isolates ethyl acetate layer.Ethyl acetate layer is further washed twice (250mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～70%) obtain 9.89g compound 1.Productive rate: 93%.
Nmr analysis:
1h NMR (300MHz, DMSO-D
6): δ 7.98 (d, 2H, J=7.2Hz), 7.72 (t, 1H, J=7.2Hz), 7.63 (t, 2H, J=7.2Hz), 7.58 (d, 1H, J=9.0Hz), 7.37 (m, 4H), 7.15 (brs, 1H), 5.77 (t, 1H, J=9.0Hz), 5.39 (d, 1H, J=7.2Hz), 5.05 (s, 1H), 5.02 (d, 1H, J=7.2Hz), 4.95 (s, 1H), 4.90 (m, 2H), 4.42 (m, 2H), 4.05 (m, 3H), 3.64 (d, 1H, J=6.6Hz), 2.33 (s, 3H), 2.28 (m, 1H), 1.83 (m, 1H), 1.66 (m, 1H), 1.61 (m, 3H), 1.52 (m, 4H), 1.36 (s, 9H), 0.96 (s, 3H), 0.85 (s, 12H), 0.08 (s, 3H), 0.02 (s, 3H),
13C?NMR(125MHz,DMSO-D
6):δ209.2,171.7,169.8,165.3,155.0,138.6,136.9,135.5,133.5,130.1,129.6,128.7,128.2,127.8,127.7,83.8,80.3,78.1,76.78,75.9,75.5,74.8,73.7,70.8,70.3,58.0,57.0,45.9,42.8,36.5,34.8,28.6,26.3,25.6,22.9,20.6,13.7,9.8,-5.3,-5.9;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
49h
68nO
14si, 922; Measured value: 922.
Embodiment 2: compound 2 synthetic
Under nitrogen protection; in 100mL round-bottomed flask, add successively 3.00g (3.25mmol) compound 1 and 30mL anhydrous tetrahydro furan solvent, be cooled to-70 ℃; then add 7.15mL (7.15mmol) two (trimethylsilyl) Lithamide tetrahydrofuran solution, stir 1 hour.Then, add 1.22g chloroformic acid benzyl ester (7.15mmol), remove refrigerant.After 2 hours, reaction nature is raised to room temperature, now adds 3.0mL acetic acid stopped reaction.Be spin-dried for, reaction mixture distributes at saturated nacl aqueous solution (100mL) and ethyl acetate (100mL), isolates ethyl acetate layer.Ethyl acetate layer is further washed twice (100mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/5～50%) obtain 3.67g compound 2.Productive rate: 95%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.12 (d, 2H, J=7.2Hz), 7.60 (t, 1H, J=7.2Hz), 7.51 (t, 2H, J=7.2Hz), 7.27 – 7.41 (m, 10H), 6.31 (m, 2H), 5.72 (d, 1H, J=7.2Hz), 5.55 (t, 1H, J=9.0Hz), 5.45 (d, 1H, J=7.2Hz), 5.31 (d, 1H, J=7.2Hz), 5.16 (m, 4H), 4.99 (d, 1H, J=9.0Hz), 4.56 (s, 1H), 4.36 (d, 1H, J=9.0Hz), 4.21 (d, 1H, J=9.0Hz), 4.00 (d, 1H, J=6.6Hz), 2.66 (m, 1H), 2.59 (s, 3H), 2.43 (m, 1H), 2.36 (m, 1H), 2.10 (m, 4H), 1.85 (s, 3H), 1.67 (m, 1H), 1.60 (s, 3H), 1.40 (m, 1H), 1.37 (s, 9H), 1.27 (s, 3H), 1.20 (s, 3H), 0.76 (s, 9H),-0.08 (s, 3H),-0.29 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.6,171.5,170.0,166.9,155.2,154.2,142.3,138.8,135.2,135.1,133.7,132.1,130.2,130.0,129.1,128.9,128.7,128.6,128.2,127.7,126.4,83.9,80.8,80.0,78.8,78.2,76.3,75.5,75.3,74.5,71.2,70.1,69.9,56.7,46.9,43.2,35.2,33.3,28.1,25.4,22.9,18.1,14.7,10.7,-5.45,-5.67;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
65h
79nO
18si, 1190; Measured value: 1190.
Embodiment 3: compound 3 synthetic
In 100mL round-bottomed flask, add successively 3.50g compound 2,10mL tetrahydrofuran (THF) and tetrabutyl ammonium fluoride (1.0mmol * 5.88mL), at room temperature, stir 2 hours.React complete, be spin-dried for, cross silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～50%) obtain 2.82g compound 3.Productive rate: 96%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.10 (d, 2H, J=7.2Hz), 7.63 (t, 1H, J=7.2Hz), 7.51 (t, 2H, J=7.2Hz), 7.32 – 7.40 (m, 10H), 6.28 (s, 1H), 6.20 (brs, 1H), 5.70 (d, 1H, J=7.2Hz), 5.54 (t, 1H, J=9.0Hz), 5.42 (d, 1H, J=7.2Hz), 5.29 (d, 1H, J=7.2Hz), 5.20 (m, 4H), 4.95 (d, 1H, J=9.0Hz), 4.66 (s, 1H), 4.32 (d, 1H, J=9.0Hz), 4.18 (d, 1H, J=9.0Hz), 3.93 (d, 1H, J=6.6Hz), 3.41 (s, 1H), 2.62 (m, 1H), 2.40 (s, 3H), 2.33 (m, 1H), 2.10 (s, 3H), 1.97 (m, 4H), 1.84 (s, 3H), 1.65 (m, 1H), 1.43 (m, 1H), 1.37 (s, 9H), 1.24 (s, 3H), 1.17 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.5,174.9,172.3,166.8,155.3,154.1,154.0,141.6,138.2,135.1,135.0,133.7,132.4,130.1,128.9,128.8,128.7,128.6,128.5,128.4,128.0,126.7,83.8,80.8,80.2,78.6,78.3,76.3,75.3,74.2,73.5,72.3,70.1,70.0,56.2,56.1,46.9,43.1,35.2,33.3,28.2,26.3,22.5,20.8,14.7,10.6;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
59h
65nO
18si, 1076; Measured value: 1076.
Embodiment 4: compound 4 synthetic
In 50mL round-bottomed flask, add successively 445mg (1.86mmol) 6-nitrine n-hexyl-diglycollic acid monoester compound, 355mg (1.86mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stir 30 minutes.Then add 1.0g (0.93mmol) compound 3 and 227mg (1.86mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 3) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～50%) obtain 0.99g compound 4.Productive rate: 82%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.12 (d, 2H, J=7.2Hz), 7.62 (t, 1H, J=7.2Hz), 7.51 (t, 2H, J=7.2Hz), 7.27 – 7.41 (m, 10H), 6.30 (s, 1H), 6.26 (brs, 1H), 5.71 (d, 1H, J=7.2Hz), 5.59 (t, 1H, J=9.0Hz), 5.52 (d, 1H, J=7.2Hz), 5.45 (s, 1H), 5.41 (d, 1H, J=7.2Hz), 5.20 (m, 4H), 4.99 (d, 1H, J=9.0Hz), 4.35 (m, 2H), 4.27 (d, 1H, J=9.0Hz), 4.11 (m, 4H), 3.97 (d, 1H, J=6.6Hz), 3.28 (t, 2H, J=7.2Hz), 2.62 (m, 1H), 2.40 (s, 3H), 2.35 (m, 1H), 2.26 (m, 1H), 2.10 (s, 3H), 1.97 (t, 1H, J=7.2Hz), 1.84 (s, 3H), 1.60 – 1.69 (m, 5H), 1.42 (m, 2H), 1.35 (s, 9H), 1.27 (s, 3H), 1.19 (s, 13H),
13C?NMR(125MHz,CDCl
3):δ201.6,169.6,168.9,167.7,166.9,155.1,154.1,142.3,136.9,135.2,135.1,133.7,132.1,130.0,128.9,128.8,128.7,128.6,128.5,128.4,128.1,126.3,83.8,80.7,80.5,78.8,78.3,76.6,75.3,74.6,74.4,72.0,70.1,69.8,68.0,67.6,64.9,56.0,53.9,51.2,46.8,43.1,34.9,33.3,28.7,28.2,28.1,26.2,25.4,22.6,19.1,14.6,10.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
69h
80n4O
22, 1317; Measured value: 1317.
Embodiment 5: compound 5 synthetic
In 100mL round-bottomed flask, add successively 500mg (3.80mmol) compound 4,20mL methyl alcohol and 50mg5% palladium-carbon, then at room temperature pass into hydrogen and stir 12 hours.React complete, reaction mixture, after filtration, is spin-dried for, at C-18 reversed-phase column through high performance liquid phase (eluent: methyl alcohol: water/10～100%) purifying obtains 295mg compound 5.Productive rate: 76%.
Nmr analysis:
1h NMR (300MHz, CD
3oD): δ 8.02 (d, 1H, J=7.0Hz), 7.57 (m, 1H), 7.50 (m, 2H), 7.31 (m, 5H), 7.18 (brs, 1H), 6.02 (m, 1H), 5.54 (d, 1H, J=6.3Hz), 5.26 (s, 1H), 5.18 (s, 1H), 4.91 (d, 1H, J=7.8Hz), 4.27 (m, 2H), 4.10 (m, 7H), 3.77 (s, 1H), 2.82 (t, 2H, J=7.0Hz), 2.35 (m, 1H), 2.31 (s, 3H), 1.88 (m, 2H), 1.82 (m, 4H), 1.73 (t, 1H, J=11.0Hz), 1.59 (s, 3H), 1.55 (m, 3H), 1.38 (m, 4H), 1.31 (s, 9H), 1.06 (s, 3H), 1.02 (s, 3H),
13C?NMR(125MHz,CD
3OD):δ209.7,170.3,170.2,169.5,168.6,166.2,156.4,138.0,135.6,133.1,130.0,129.8,128.5,128.3,127.8,126.8,84.5,80.9,79.5,77.7,76.2,75.3,75.0,74.3,72.1,71.3,67.4,67.2,64.5,57.5,54.8,46.6,43.1,39.24,36.1,35.2,28.0,27.7,27.0,25.6,25.0,22.2,20.2,13.2,9.2;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
53h
70n
2o
18, 1023; Measured value: 1023.
Embodiment 6: covalent polymer 6 synthetic
In 10mL round-bottomed flask, by 100mg dextran (molecular-weight average is～7000) and 20mg N, N'-carbonyl dimidazoles is dissolved in 1.0mL dimethyl sulfoxide (DMSO) and is heated to 60 ℃ of activation 30 minutes, then adds 20mg compound 5 and 50uL triethylamine, stirs 12 hours.React complete, reaction mixture methanol extraction, filters, and by methanol wash 3 times, throw out is dissolved in 2.0mL distilled water, then dialyses putting into dialysis tubing.Dialyse complete, through lyophilize, obtain 76mg covalent polymer 6.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures containing Docetaxel 8% (w/w).
Synthetic route 2
Reaction conditions and reagent:
A) two (trimethylsilyl) Lithamide/allyl chlorocarbonate, anhydrous tetrahydro furan ,-70 ℃, 1h;
B) tetrabutyl ammonium fluoride, tetrahydrofuran (THF), room temperature, 2h;
C) 6-(N-allyloxy) formamido group-n-hexyl-diglycollic acid monoamide/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
D) palladium-carbon/hydrogen, methyl alcohol, room temperature, 12h;
E) N, N'-carbonyl dimidazoles/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h.
Embodiment 7: compound 7 synthetic
Under nitrogen protection; in 250mL round-bottomed flask, add successively 8.00g (8.68mmol) compound 1 and 60mL anhydrous tetrahydro furan solvent, be cooled to-70 ℃; then add (22.0mL * 1.0mmol) two (trimethylsilyl) Lithamide tetrahydrofuran solution, stir 1 hour.Then, add 2.30mL allyl chlorocarbonate (22.0mmol), remove refrigerant.After 2 hours, reaction nature is raised to room temperature, now adds 5.0mL acetic acid stopped reaction.Be spin-dried for, reaction mixture distributes at saturated nacl aqueous solution (100mL) and ethyl acetate (100mL), isolates ethyl acetate layer.Ethyl acetate layer is further washed twice (100mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/5～50%) obtain 9.10g compound 7.Productive rate: 96%.
Nmr analysis:
1h NMR (300MHz, DMSO-D
6): δ 7.97 (d, 2H, J=7.2Hz), 7.85 (t, 1H, J=7.2Hz), 7.61 (m, 3H), 7.39 (m, 4H), 7.16 (t, 1H, J=7.2Hz), 6.03 (s, 1H), 5.94 (m, 2H), 5.79 (t, 1H, J=9.0Hz), 5.42 (d, 1H, J=7.2Hz), 5.23-5.37 (m, 5H), 5.00 (d, 1H, J=8.4Hz), 4.90 (t, 1H, J=8.4Hz), 4.76 (s, 1H), 4.61 (m, 2H), 4.55 (m, 2H), 4.43 (d, 1H, J=7.8Hz), 4.06 (s, 2H), 3.67 (d, 1H, J=7.2Hz), 2.47 (m, 3H), 2.37 (s, 3H), 1.83 (m, 1H), 1.76 (t, 1H, J=12.0Hz), 1.73 (s, 3H), 1.65 (s, 3H), 1.60 (m, 1H), 1.36 (s, 9H), 0.99 (s, 3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.06 (s, 3H),
13C?NMR(125MHz,DMSO-D
6):δ201.7,171.7,170.2,165.2,155.1,153.2,141.1,138.5,133.7,132.2,132.1,131.9,129.7,129.6,128.8,128.3,127.8,119.0,118.6,82.8,79.7,78.2,77.7,76.6,75.8,75.3,75.0,73.9,69.9,68.5,58.0,55.5,46.0,42.8,34.3,32.9,28.2,25.6,22.8,21.1,17.9,14.3,10.4,-5.2,-5.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
57h
75nO
18si, 1090; Measured value: 1090.
Embodiment 8: compound 8 synthetic
In 100mL round-bottomed flask, add successively 9.0g (8.26mmol) compound 7,30mL tetrahydrofuran (THF) and tetrabutyl ammonium fluoride (15.0mL * 1.0mmol), at room temperature, stir 2 hours.React complete, be spin-dried for, cross silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～50%) obtain 7.49g compound 8.Productive rate: 93%.
Nmr analysis:
1h NMR (300MHz, DMSO-D
6): δ 7.99 (d, 2H, J=7.2Hz), 7.71 (t, 1H, J=7.2Hz), 7.63 (d, 2H, J=7.2Hz), 7.45 (d, 1H, J=9.0Hz), 7.37 (t, 1H, J=7.8Hz), 7.31 (d, 2H, J=7.2Hz), 7.21 (t, 1H, J=7.2Hz), 6.07 (s, 1H), 5.87-5.98 (m, 3H), 5.45 (d, 1H, J=7.2Hz), 5.21-5.38 (m, 5H), 4.98 (d, 1H, J=9.0Hz), 4.91 (t, 1H, J=9.0Hz), 4.83 (s, 1H), 4.63 (m, 2H), 4.57 (d, 2H, J=6.0Hz), 4.38 (d, 1H, J=6.0Hz), 4.05 (m, 2H), 3.69 (d, 1H, J=7.2Hz), 2.46 (m, 1H), 2.26 (s, 3H), 1.94 (m, 1H), 1.83 (m, 1H), 1.82 (s, 3H), 1.74 (t, 1H, J=12.0Hz), 1.65 (s, 3H), 1.35 (s, 9H), 1.04 (s, 3H), 0.98 (s, 3H),
13C?NMR(125MHz,DMSO-D
6):δ201.7,172.9,170.5,165.5,155.2,153.3,141.7,139.6,133.7,132.4,132.0,131.8,129.8,128.8,128.3,127.4,127.3,119.0,118.6,83.1,79.8,78.5,77.8,76.7,75.3,75.0,73.8,73.7,69.7,68.5,57.4,55.6,46.2,43.0,34.6,32.9,28.2,26.2,22.4,20.5,14.1,10.1;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
51h
62nO
18, 976; Measured value: 976.
Embodiment 9: compound 9 synthetic
In 50mL round-bottomed flask, add successively 291mg (0.92mmol) 6-(N-allyloxy) formamido group-n-hexyl-diglycollic acid monoamide, 147mg (0.77mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stir 30 minutes.Then add 300mg (0.31mmol) compound 8 and 75mg (0.62mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 3) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: chloroform: methyl alcohol/0～5%) obtain 281mg compound 9.Productive rate: 71%.
Nmr analysis:
1h NMR (300MHz, DMSO-D
6): δ 7.98 (d, 2H, J=7.2Hz), 7.81 (brs, 2H), 7.72 (t, 1H, J=7.2Hz0, 7.62 (t, 2H, J=7.2Hz), 7.51 (d, 1H, J=9.0Hz), 7.38 (t, 2H, J=7.2Hz), 7.31 (d, 2H, J=7.2Hz), 7.20 (m, 2H), 6.06 (s, 1H), 5.95 (m, 3H), 5.44 (s, 1H), 5.22 – 5.42 (m, 6H), 5.15 (d, 1H, J=9.0Hz), 4.98 (d, 1H, J=9.0Hz), 4.89 (s, 1H), 4.85 (s, 1H), 4.50 – 4.70 (m, 4H), 4.44 (m, 4H), 4.35 (m, 1H), 4.21 (s, 4H, 4.05 (m, 2H), 3.92 (m, 5H), 3.86 (s, 1H), 3.75 (s, 1H), 3.17 (s, 1H), 3.07 (t, 2H, J=7.2Hz), 2.95 (t, 2H, J=7.2Hz), 2.49 (m, 1H), 2.25 (s, 3H), 2.02 (m, 1H), 1.99 (m, 1H), 1.81 (s, 3H), 1.74 (t, 1H, J=12.0Hz), 1.63 (s, 3H), 1.45 (m, 6H), 1.35 (s, 9H), 1.23 (m, 4H), 1.03 (s, 3H), 0.97 (s, 3H),
13C?NMR(125MHz,DMSO-D
6):δ203.1,172.2,170.8,170.6,168.7,165.6,155.7,155.6,153.6,142.1,139.9,134.3,134.0,132.5,132.3,130.5,130.0,129.2,128.6,127.7,119.4,119.0,116.9,83.1,81.7,80.0,78.5,78.2,77.1,75.6,75.4,73.0,72.3,71.8,70.5,69.9,68.8,68.1,57.4,55.8,46.5,43.2,38.4,38.3,35.1,34.9,33.3,30.0,29.7,28.1,27.7,25.5,22.8,22.5,21.6,14.5,10.8;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
65h
83n3O
23, 1274; Measured value: 1274.
Embodiment 10: compound 10 synthetic
In 100mL round-bottomed flask, add successively 200mg (0.16mmol) compound 9,10mL methyl alcohol and 30mg5% palladium-carbon, then at room temperature pass into hydrogen and stir 12 hours.React complete, reaction mixture, after filtration, is spin-dried for, at C-18 reversed-phase column through high performance liquid phase (eluent: methyl alcohol: water/10～100%) purifying obtains 125mg compound 10.Productive rate: 75%.
Nmr analysis:
1h NMR (300MHz, CD
3oD): δ 8.10 (s, 2H), 7.62 (s, 1H), 7.56 (s, 2H), 7.30 – 7.50 (m, 5H), 7.25 (s, 1H), 6.10 (s, 1H), 5.62 (s, 1H), 5.34 (s, 2H), 4.39 (m, 1H), 4.36 (m, 1H), 4.17 (m, 3H), 4.00 (m, 2H), 3.85 (s, 1H), 3.22 (m, 2H), 2.90 (m, 2H), 2.40 (m, 4H), 2.21 (m, 1H), 1.97 (m, 4H), 1.83 (m, 1H), 1.67 (m, 5H), 1.55 (m, 3H), 1.40 (m, 4H), 1.39 (s, 9H), 1.14 (s, 3H), 1.11 (s, 3H),
13C?NMR(125MHz,CD
3OD):δ211.2,171.7,171.6,171.4,170.1,167.9,157.9,139.5,138.9,138.2,134.8,133.6,131.5,131.2,130.7,130.2,129.9,129.3,129.1,128.4,86.1,82.5,81.1,79.2,77.7,76.9,76.5,75.8,73.6,72.9,71.6,69.1,59.1,56.3,48.1,44.6,40.77,39.8,37.63,36.7,30.4,29.1,28.6,27.4,27.1,23.4,21.8,14.8,10.6;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
53h
71n3O
17, 1022; Measured value: 1022.
Embodiment 11: covalent polymer 11 synthetic
In 10mL round-bottomed flask, by 100mg dextran (molecular-weight average is～7000) and 20mg N, N'-carbonyl dimidazoles is dissolved in 1.0mL dimethyl sulfoxide (DMSO) and is heated to 60 ℃ of activation 30 minutes, then adds 30mg compound 10 and 50uL triethylamine, stirs 12 hours.React complete, reaction mixture methanol extraction, filters, and by methanol wash 3 times, throw out is dissolved in 2.0mL distilled water, then dialyses putting into dialysis tubing.Dialyse complete, through lyophilize, obtain 76mg product.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures containing Docetaxel 10% (w/w).
Synthetic route 3
Reaction conditions and reagent:
A) benzyl succinate monoester/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
B) palladium-carbon/hydrogen, methyl alcohol, room temperature, 12h;
C) N, N'-carbonyl dimidazoles/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h;
D) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/I-hydroxybenzotriazole (HOBt)/DIPEA, dimethyl sulfoxide (DMSO), room temperature, 2h.
Embodiment 12: compound 12 synthetic
In 50mL round-bottomed flask, add successively 125mg (0.56mmol) benzyl succinate monoester, 107mg (0.56mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stirs 30 minutes.Then add 300mg (0.28mmol) compound 3 and 68mg (0.56mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 3) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: chloroform: methyl alcohol/0～5%) obtain 305mg compound 12.Productive rate: 86%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.12 (d, 2H, J=7.2Hz), 7.63 (t, 1H, J=7.2Hz), 7.52 (t, 2H, J=7.2Hz), 7.27 – 7.40 (m, 20H), 6.31 (s, 1H), 6.24 (m, 1H), 5.71 (d, 1H, J=7.2Hz), 5.58 (t, 1H, J=9.0Hz), 5.48 (d, 1H, J=7.2Hz), 5.44 (d, 1H, J=7.2Hz), 5.36 (s, 1H), 5.22 (m, 2H), 5.20 (m, 4H), 4.99 (d, 1H, J=9.0Hz), 4.35 (d, 1H, J=9.0Hz), 4.18 (d, 1H, J=9.0Hz), 4.13 (dd, 1H, J=14.6, 7.2Hz), 4.05 (d, 1H, J=6.6Hz), 3.98 (d, 1H, J=6.0Hz), 3.41 (s, 1H), 2.77 (m, 1H), 2.68 (m, 4H), 2.46 (s, 3H), 2.35 (m, 1H), 2.24 (m, 1H), 2.10 (m, 4H), 1.97 (t, 1H, J=6.6Hz), 1.84 (s, 3H), 1.65 (m, 1H), 1.43 (m, 1H), 1.36 (s, 9H), 1.24 (s, 3H), 1.19 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.7,171.7,171.0,169.7,168.0,166.9,155.2,154.1,142.6,137.2,135.6,135.3,135.1,133.7,131.9,130.2,129.0,128.9,128.7,128.6,128.5,128.4,128.3,128.2,126.4,83.8,80.7,80.4,78.8,78.3,76.3,75.3,74.5,71.7,69.9,66.7,56.0,54.0,46.9,43.1,35.0,33.3,28.9,28.8,28.1,26.2,22.6,21.2,14.6,10.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
70h
75nO
21, 1266; Measured value: 1266.
Embodiment 13: compound 13 synthetic
In 100mL round-bottomed flask, add successively 250mg (0.20mmol) compound 9,20mL methyl alcohol and 50mg5% palladium-carbon, then at room temperature pass into hydrogen and stir 12 hours.React complete, reaction mixture after filtration, is spin-dried for, at C-18 reversed-phase column through high performance liquid phase (eluent: methyl alcohol: water/10～100%) purifying obtains 157mg compound 13.Productive rate: 81%.
Nmr analysis:
1h NMR (500MHz, CD
3oD): δ 8.15 (s, 2H), 7.56 (s, 1H), 7.52 (s, 2H), 7.26 – 7.33 (m, 5H), 6.11 (s, 1H), 6.24 (m, 1H), 5.60 (s, 1H), 5.33 (s, 1H), 5.24 (s, 1H), 5.17 (s, 1H), 4.94 (s, 1H), 4.24 (s, 1H), 4.15 (s, 2H), 3.81 (s, 1H), 3.53 (m, 2H), 2.77 (m, 1H), 2.68 (m, 4H), 2.35 (s, 3H), 2.22 (m, 1H), 1.90 (m, 1H), 1.85 (m, 4H), 1.65 (s, 3H), 1.55 (m, 4H), 1.30 (s, 9H), 1.14 (m, 1H), 0.85 (s, 3H), 0.84 (s, 3H),
13C?NMR(125MHz,CD
3OD):δ211.0,174.3,169.7,168.4,166.8,155.5,138.8,137.1,135.6,133.5,130.9,129.3,128.8,128.5,128.1,126.4,84.6,81.0,80.3,78.1,76.5,75.0,75.6,74.2,72.1,71.2,57.5,54.1,46.3,43.0,36.2,35.2,28.6,27.9,27.0,22.4,20.7,13.4,9.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
47h
57nO
17, 908; Measured value: 908.
Embodiment 14: covalent polymer 14 synthetic
In 20mL round-bottomed flask, by 1.0g dextran (molecular-weight average is～12,000) and 150mg N, N'-carbonyl dimidazoles is dissolved in 3.0mL dimethyl sulfoxide (DMSO) and is heated to 60 ℃ of activation 30 minutes, then add 300mg1, the positive quadrol of 6-, dimethyl sulfoxide (DMSO) stirs 12 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times, the dry 1.1g compound 14 that to obtain.
Embodiment 15: covalent polymer 15 synthetic
In 10mL round-bottomed flask, by 100mg covalent polymer 14,20mg N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC), 15mg1-hydroxybenzotriazole (HOBt), 35mg compound 13, and 100uL DIPEA is dissolved in 1.5mL dimethyl sulfoxide (DMSO), at room temperature stir 2 hours.React complete, reaction mixture methanol extraction, filters, and by methanol wash 3 times, throw out is dissolved in 2.0mL distilled water, then dialyses putting into dialysis tubing.Dialyse complete, through lyophilize, obtain 81mg covalent polymer 15.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures containing Docetaxel 25% (w/w).
Synthetic route 4
Reaction conditions and reagent:
A) 2-[2-(allyloxy formamido group) acetamido] acetic acid/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
B) two (triphenylphosphine) palladium chloride/acetic acid/tributyl tin hydrogen, chloroform, room temperature, 2h;
C) N, N'-carbonyl dimidazoles/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h.
Embodiment 16: compound 16 synthetic
In 50mL round-bottomed flask, add successively 105mg (0.61mmol) 2-[2-(allyloxy formamido group) acetamido] acetic acid, 117mg (0.61mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stir 30 minutes.Then add 200mg (0.21mmol) compound 8 and 50mg (0.41mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed three times (20mL * 3) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: chloroform: methyl alcohol/0～10%) obtain 225mg compound 16.Productive rate: 91%.
Nmr analysis:
1h NMR (500MHz, DMSO-D
6): δ 8.15 (d, 2H, J=7.2Hz), 7.69 (t, 1H, J=7.2Hz), 7.63 (d, 1H, J=7.2Hz), 7.56 (t, 2H, J=7.2Hz), 7.44 (m, 4H), 7.29 (brs, 1H), 6.22 (s, 1H), 6.10 (s, 1H), 5.95 (m, 3H), 5.66 (d, 1H, J=7.2Hz), 5.66 (t, 1H, J=7.2Hz), 5.28-5.342 (m, 4H), 5.21 (m, 2H), 5.02 (d, 1H, J=9.0Hz), 4.57-4.67 (m, 4H), 4.23 (m, 2H), 4.18 (m, 2H), 3.89 (s, 1H), 3.87 (s, 1H), 2.56 (m, 1H), 2.46 (s, 3H), 2.27 (m, 1H), 2.05 (m, 1H), 1.96 (s, 3H), 1.84 (t, 1H, J=12.0Hz), 1.79 (s, 3H), 1.43 (s, 9H), 1.16 (s, 3H), 1.13 (s, 3H),
13C?NMR(125MHz,CD
3OD):δ202.3,171.5,170.7,170.3,169.1,168.6,166.1,157.5,156.4,153.9,142.1,137.3,133.2,132.8,132.5,131.9,131.7,129.8,128.5,128.3,128.0,126.8,117.6,117.3,116.4,83.6,80.3,79.2,78.2,77.4,75.8,75.3,75.2,74.3,71.6,68.6,68.4,65.4,55.8,54.7,46.3,43.8,43.5,34.8,33.1,29.1,28.7,26.2,21.9,20.8,13.6,9.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
59h
71n3O
22, 1174; Measured value: 1174.
Embodiment 17: compound 17 synthetic
Under nitrogen protection; in 25mL round-bottomed flask; add successively 200mg (0.17mmol) compound 16; 5.0mL anhydrous chloroform; 100uL acetic acid; two (triphenylphosphine) palladium chlorides of 18mg (0.26mmol) and 248mg (0.85mmol) tributyl tin hydrogen, then at room temperature stir 2 hours.React complete, reaction mixture, is spin-dried for, at C-18 reversed-phase column through high performance liquid phase (eluent: methyl alcohol: water/10～100%) purifying obtains 115mg compound 17.Productive rate: 72%.
Nmr analysis:
1h NMR (500MHz, CD
3oD): δ 8.12 (d, 2H, J=7.2Hz), 7.74 (t, 1H, J=7.2Hz), 7.66 (m, 1H), 7.42 (m, 3H), 7.27 (m, 1H), 6.01 (brs, 1H), 5.64 (d, 1H, J=7.2Hz), 5.35 (s, 1H), 5.25 (s, 1H), 5.19 (s, 1H), 5.00 (d, 1H, J=7.2Hz), 4.19 (m, 5H), 3.86 (d, 1H, J=7.2Hz), 3.73 (s, 1H), 2.43 (m, 1H), 2.39 (s, 3H), 2.23 (m, 1H), 1.94 (m, 1H), 1.92 (s, 1H), 1.68 (s, 3H), 1.41 (s, 9H), 1.23 (m, 1H), 1.12 (s, 1H), 1.08 (s, 1H),
13C?NMR(125MHz,CD
3OD):δ209.7,170.1,169.1,168.6,166.5,166.3,156.4,138.5,137.3,136.5,133.2,132.4,131.2,130.9,130.0,129.6,128.6,128.0,127.8,126.8,84.5,80.1,79.5,77.7,76.2,75.6,74.8,74.0,72.0,71.4,57.4,54.4,46.5,43.1,40.0,39.6,36.1,35.1,27.2,26.4,22.0,20.2,13.1,9.0;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
47h
59n
3o
16, 922; Measured value: 922.
Embodiment 18: covalent polymer 18 synthetic
In 10mL round-bottomed flask, by 80mg dextran (molecular-weight average is～7000) and 15mg N, N'-carbonyl dimidazoles is dissolved in 1.0mL dimethyl sulfoxide (DMSO) and is heated to 50 ℃ of activation 30 minutes, then adds 15mg compound 17 and 50uL triethylamine, stirring at room 12 hours.React complete, reaction mixture methanol extraction, filters, and by methanol wash 3 times, throw out is dissolved in 2.0mL distilled water, then dialyses putting into dialysis tubing.Dialyse complete, through lyophilize, obtain 65mg covalent polymer 18.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures containing Docetaxel 11% (w/w).
Synthetic route 5
Reaction conditions and reagent:
A) TERT-BUTYL DIMETHYL CHLORO SILANE/imidazoles, dimethyl formamide, room temperature, 24h;
B) two (trimethylsilyl) Lithamide/allyl chlorocarbonate, anhydrous tetrahydro furan ,-70 ℃, 1h;
C) tetrabutyl ammonium fluoride, tetrahydrofuran (THF), room temperature, 2h;
D) 2-[2-oxygen-(4-alkynes amylamine base) oxyethyl group] acetic acid/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
E) tetrakis triphenylphosphine palladium/1,3-dimethyl barbituric acid, chloroform, room temperature, 2h;
F) 6-azido--n-caproic acid/copper sulfate/vitamin C sodium salt, dimethyl sulfoxide (DMSO), room temperature, 12h;
G) 5-alkynes-n-caproic acid/acetic acid/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
H) tetrabutyl ammonium fluoride, tetrahydrofuran (THF), room temperature, 2h; I) 6-azido--n-caproic acid/copper sulfate/vitamin C sodium salt, dimethyl sulfoxide (DMSO), room temperature, 12h;
J) 4-alkynes penta aminodiglycol acid monoamide/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
K) tetrakis triphenylphosphine palladium/1,3-dimethyl barbituric acid, chloroform, room temperature, 2h;
L) copper sulfate/vitamin C sodium salt, dimethyl sulfoxide (DMSO), room temperature, 12h;
M) 6-azido--n-caproic acid/N, N'-carbonyl dimidazoles/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h;
N) copper sulfate/vitamin C sodium salt, dimethyl sulfoxide (DMSO), room temperature, 12h.
Embodiment 19: compound 19 synthetic
In 250mL round-bottomed flask, add successively 7.0g (8.19mmol) taxol, 1.60g (24.57mmol) imidazoles and 20mL solvent dimethylformamide, then add 3.70g (24.57mmol) TERT-BUTYL DIMETHYL CHLORO SILANE.At room temperature, stir 12 hours.React complete, reaction mixture distributes at saturated nacl aqueous solution (250mL) and ethyl acetate (250mL), isolates ethyl acetate layer.Ethyl acetate layer is further washed twice (250mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～60%) obtain 7.61g compound 19.Productive rate: 96%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.15 (d, 2H, J=7.2Hz), 7.74 (d, 2H, J=7.2Hz), 7.62 (t, 2H, J=7.2Hz), 7.51 (m, 3H), 7.41 (m, 4H), 7.33 (m, 3H), 7.09 (d, 1H, J=9.0Hz), 6.29 (m, 2H), 5.76 (d, 1H, J=9.0Hz), 5.70 (d, 1H, J=9.0Hz), 4.99 (d, 1H, J=9.0Hz), 4.67 (s, 1H), 4.45 (brs, 1H), 4.34 (d, 1H, J=9.0Hz), 4.23 (d, 1H, J=9.0Hz), 3.84 (d, 1H, J=7.2Hz), 2.58 (m, 4H), 2.51 (s, 1H), 2.41 (m, 1H), 2.25 (s, 3H), 2.15 (m, 1H), 1.89 (s, 3H), 1.82 (m, 1H), 1.71 (s, 3H), 1.26 (s, 3H), 1.15 (s, 3H), 0.81 (s, 9H),-0.02 (s, 3H),-0.27 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ203.7,173.3,171.3,170.1,167.0,166.9,142.1,138.2,134.0,133.7,132.9,131.8,130.2,129.1,128.7,128.0,127.0,126.4,84.4,81.1,79.1,76.5,75.5,75.2,75.0,72.1,71.4,58.5,55.6,45.5,43.2,35.8,35.5,26.7,25.5,23.2,22.2,20.8,18.1,14.9,9.6,-5.3,-5.8;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
53h
65n3O
14si, 968; Measured value: 968.
Embodiment 20: compound 20 synthetic
Under nitrogen protection; in 250mL round-bottomed flask, add successively 6.0g (6.20mmol) compound 19 and 60mL anhydrous tetrahydro furan solvent, be cooled to-70 ℃; then add two (trimethylsilyl) Lithamide tetrahydrofuran solutions (7.50mL * 1.0M), stir 1 hour.Then, add 800uL allyl chlorocarbonate (7.50mmol), remove refrigerant.After 2 hours, reaction nature is raised to room temperature, now adds 2.0mL acetic acid stopped reaction.Be spin-dried for solvent, reaction mixture distributes at saturated nacl aqueous solution (100mL) and ethyl acetate (100mL), isolates ethyl acetate layer.Ethyl acetate layer is further washed twice (100mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/5～50%) obtain 6.18g compound 20.Productive rate: 95%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.12 (d, J=7.2Hz, 2H), 7.74 (d, J=7.2Hz, 2H), 7.61 (t, J=7.2Hz, 2H), 7.53 (m, 3H), 7.41 (m, 4H), 7.31 (m, 3H), 7.13 (d, J=9.0Hz, 1H), 6.39 (s, 1H), 6.26 (t, J=9.0Hz, 1H), 5.98 (m, 1H), 5.74 (d, J=9.0Hz, 1H), 5.70 (d, J=7.2Hz, 1H), 5.36 (dd, J=10.2, 7.8Hz, 1H), 5.32 (d, J=15.6Hz, 1H), 5.22 (d, J=15.6Hz, 1H), 5.00 (d, J=9.6Hz, 1H), 4.73 (m, 1H), 4.67 (s, 1H), 4.65 (m, 1H), 4.34 (d, J=9.0Hz, 1H), 4.21 (d, J=9.0Hz, 1H), 3.98 (d, J=6.6Hz, 1H), 2.63 (m, 1H), 2.58 (s, 3H), 2.41 (dd, J=15.0, 9.0Hz, 1H), 2.21 (dd, 1H, J=15.0, 9.0Hz), 2.16 (s, 3H), 2.02 (s, 3H), 1.98 (m, 1H), 1.82 (s, 3H), 1.27 (s, 3H), 1.17 (s, 3H), 0.81 (s, 9H),-0.03 (s, 3H),-0.29 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.6,171.5,169.9,168.9,167.1,166.8,154.0,140.9,138.2,134.0,133.7,132.8,131.8,130.2,130.1,129.0,128.7,128.3,127.0,126.4,118.8,83.8,81.1,78.7,76.4,75.3,75.2,75.0,74.4,72.4,69.1,56.0,55.6,45.6,43.1,36.6,35.5,26.3,25.9,23.0,21.4,20.7,18.2,14.1,10.7,-5.3,-5.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
57h
70nO
16si, 1052; Measured value: 1052.
Embodiment 21: compound 21 synthetic
In 100mL round-bottomed flask, add successively 6.0g (5.70mmol) compound 20,20.0mL tetrahydrofuran (THF) and tetrabutyl ammonium fluoride (11.40mL * 1.0M), at room temperature, stir 2 hours.React complete, be spin-dried for, cross silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～60%) obtain 5.02g compound 21.Productive rate: 94%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.11 (d, 2H, J=7.2Hz), 7.76 (d, 2H, J=7.2Hz), 7.61 (t, 2H, J=7.2Hz), 7.30 – 7.51 (m, 10H), 7.12 (d, 1H, J=9.0Hz), 6.35 (s, 1H), 6.18 (t, 1H, J=9.0Hz), 5.95 (m, 1H), 5.80 (d, 1H, J=9.0Hz), 5.66 (d, 1H, J=7.2Hz), 5.46 (m, 1H), 5.35 (d, 1H, J=12.0Hz), 5.24 (d, 1H, J=12.0Hz), 4.94 (d, 1H, J=9.0Hz), 4.79 (s, 1H), 4.70 (m, 1H), 4.65 (m, 1H), 4.30 (d, 1H, J=8.4Hz), 4.17 (d, 1H, J=8.4Hz), 4.09 (dd, 1H, J=15.0, 7.2Hz), 3.91 (d, 1H, J=7.2Hz), 2.60 (m, 1H), 2.39 (s, 3H), 2.33 (m, 1H), 2.15 (m, 4H), 1.96 (t, 1H, J=12.0Hz), 1.85 (s, 3H), 1.83 (m, 1H), 1.81 (s, 3H), 1.20 (s, 3H), 1.17 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.6,172.4,171.2,170.4,167.0,166.8,154.0,140.5,138.0,133.8,133.7,133.1,131.9,131.8,130.2,130.1,129.0,128.9,128.7,128.3,127.1,118.9,83.4,80.9,78.5,76.4,75.4,75.3,74.3,73.2,72.1,69.2,54.9,46.9,43.2,35.5,33.4,26.5,22.54,21.1,20.8,14.2,10.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
51h
56nO
16, 938; Measured value: 938.
Embodiment 22: compound 22 synthetic
In 50mL round-bottomed flask, add successively 66mg (0.64mmol) 5-alkynes n-caproic acid, 122mg (0.64mmol) N-(3-dimethylamino-propyl)-N-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stirs 30 minutes.Then add 300mg (0.32mmol) compound 21 and 78mg (0.64mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～50%) obtain 287mg compound 22.Productive rate: 87%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.02 (d, 2H, J=7.2Hz), 7.66 (d, 2H, J=7.2Hz), 7.52 (t, 2H, J=7.2Hz), 7.41 (m, 3H), 7.25 – 7.33 (m, 7H), 6.83 (d, 1H, J=7.8Hz), 6.29 (s, 1H), 6.13 (t, 1H, J=9.0Hz), 5.87 (m, 2H), 5.60 (d, 1H, J=6.0Hz), 5.42 (m, 2H), 5.23 (d, 1H, J=12.0Hz), 5.14 (d, 1H, J=12.0Hz), 4.88 (d, 1H, J=9.0Hz), 4.61 (m, 1H), 4.54 (m, 1H), 4.23 (d, 1H, J=7.2Hz), 4.08 (d, 1H, J=7.2Hz), 3.87 (d, 1H, J=6.0Hz), 2.55 (m, 2H), 2.42 (m, 1H), 2.39 (s, 3H), 2.28 (m, 1H), 2.22 (m, 1H), 2.15 (m, 2H), 2.05 (s, 3H), 1.95 (s, 3H), 1.88 (m, 2H), 1.76 (m, 2H), 1.75 (s, 3H), 1.11 (s, 3H), 1.07 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.8,172.6,170.2,168.5,168.1,167.2,166.9,153.9,141.3,136.7,133.8,133.7,133.0,132.1,131.9,130.2,129.1,128.8,128.5,128.0,127.1,126.6,118.8,84.0,83.3,80.8,79.2,76.4,75.4,75.3,74.5,73.4,71.8,69.5,69.1,56.1,53.5,47.0,43.3,35.4,33.4,32.3,26.5,23.4,22.7,21.4,20.8,17.5,14.6,10.8;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
57h
61nO
17, 1032; Measured value: 1032.
Embodiment 23: compound 23 synthetic
In 25mL round-bottomed flask, add successively 200mg (0.19mmol) compound 22,11mg (0.01mmol) tetrakis triphenylphosphine palladium, 44mg (0.28mmol) 1,3-dimethyl barbituric acid, 5.0mL anhydrous tetrahydro furan, then at room temperature stirs 2 hours.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～70%) purifying obtains 162mg compound 23.Productive rate: 90%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.15 (d, 2H, J=7.2Hz), 7.75 (d, 2H, J=7.2Hz), 7.62 (d, 2H, J=7.2Hz), 7.52 (m, 3H), 7.35 – 7.45 (m, 7H), 6.92 (d, 1H, J=9.0Hz), 6.31 (s, 1H), 6.27 (t, 1H, J=9.0Hz), 5.96 (d, 1H, J=7.2Hz), 5.70 (d, 1H, J=6.6Hz), 5.52 (s, 1H), 4.99 (d, 1H, J=9.0Hz), 4.46 (s, 1H), 4.32 (d, 1H, J=9.0Hz), 4.08 (d, 1H, J=9.0Hz), 3.83 (d, 1H, J=7.2Hz), 2.62 (m, 1H), 2.52 (m, 2H), 2.51 (s, 3H), 2.39 (m, 1H), 2.30 (m, 1H), 2.24 (s, 3H), 2.19 (m, 2H), 1.96 (s, 3H), 1.85 (m, 4H), 1.75 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ203.8,172.1,171.3,169.8,168.0,167.8,167.0,142.7,136.9,133.7,132.7,132.0,129.1,129.0,128.7,128.5,127.1,126.5,84.3,82.9,81.0,79.1,76.4,75.5,75.0,73.9,72.1,71.8,69.5,58.4,52.7,45.5,43.1,35.5,32.2,26.8,23.3,22.6,20.8,17.8,14.8,9.6;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
53h
57nO
15, 948; Measured value: 948.
Embodiment 24: compound 24 synthetic
In 10mL round-bottomed flask, add successively 35mg (0.04mmol) compound 23,50mg (0.32mmol) 6-azido--n-caproic acid, 2.0mL methyl alcohol, copper-bath (30uL * 1.0M) and sodium ascorbate salts solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: chloroform: methyl alcohol/0～10%) purifying obtains 34mg compound 24.Productive rate: 82%.
Nmr analysis:
1h NMR (500MHz, CD
3oD): δ 8.02 (d, 2H, J=7.2Hz), 7.71 (d, 2H, J=7.2Hz), 7.57 (m, 2H), 7.49 (t, 2H, J=7.2Hz), 7.42 (t, 2H, J=7.2Hz), 7.39 (m, 2H), 7.34 (m, 4H), 7.16 (t, 1H, J=7.2Hz), 6.35 (s, 1H), 5.98 (t, 1H, J=6.0Hz), 5.54 (d, 1H, J=6.0Hz), 5.38 (d, 1H, J=6.0Hz), 4.91 (d, 1H, J=9.0Hz), 4.23 (m, 4H), 4.08 (s, 2H), 3.71 (d, 1H, J=7.2Hz), 3.21 (s, 2H), 2.62 (m, 2H), 2.37 (m, 2H), 2.30 (s, 3H), 2.10 (m, 1H), 2.05 (s, 3H), 1.89 (m, 3H), 1.83 (s, 3H), 1.77 (m, 2H), 1.72 (m, 2H), 1.55 (s, 9H), 1.51 (m, 3H), 1.22 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ203.8,175.9,172.6,174.2,174.0,169.2,169.1,166.3,146.6,141.0,137.0,134.1,133.5,133.2,131.5,130.0,129.8,129.1,128.7,128.6,128.3,128.1,127.2,127.1,122.1,84.5,80.9,77.6,75.4,74.8,74.5,74.2,71.6,70.9,57.8,53.9,49.7,46.5,47.2,36.1,35.0,33.2,29.6,26.4,26.1,24.7,24.5,23.8,22.1,21.2,20.5,13.2,9.3;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
59h
68n4O
17, 1105; Measured value: 1105.
Embodiment 25: compound 25 synthetic
In 50mL round-bottomed flask, add successively 74mg (0.72mmol) 5-alkynes n-caproic acid, 138mg (0.72mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stirs 30 minutes.Then add 350mg (0.36mmol) compound 19 and 87mg (0.72mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～45%) obtain 329mg compound 25.Productive rate: 86%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.03 (d, 2H, J=7.2Hz), 7.65 (d, 2H, J=7.2Hz), 7.51 (t, 2H, J=7.2Hz), 7.41 (m, 3H), 7.30 (m, 4H), 7.22 (m, 3H), 7.01 (d, 1H, J=1.8Hz), 6.16 (m, 2H), 5.63 (d, 1H, J=9.0Hz), 5.61 (d, 1H, J=7.2Hz), 5.52 (dd, 1H, J=9.0, 7.2Hz), 4.89 (d, 1H, J=9.0Hz), 4.57 (s, 1H), 4.25 (d, 1H, J=9.0Hz), 4.11 (d, 1H, J=9.0Hz), 3.87 (d, 1H, J=7.2Hz), 2.51 (m, 1H), 2.50 (s, 3H), 2.36 (m, 4H), 2.15 (m, 3H), 2.02 (s, 3H), 1.96 (s, 1H), 1.85 (m, 2H), 1.76 (m, 3H), 1.71 (s, 3H), 1.24 (s, 3H), 1.13 (s, 3H), 0.78 (s, 9H),-0.04 (s, 3H),-0.4 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ202.1,172.3,171.4,169.9,168.9,167.2,167.0,141.0,138.2,134.4,133.8,132.7,131.8,130.2,129.1,128.8,127.9,127.0,126.2,84.0,83.4,81.0,78.6,76.4,75.4,75.2,74.5,71.4,71.2,68.8,46.8,43.4,35.6,33.4,32.9,26.3,25.4,23.2,21.4,20.7,17.8,14.7,10.9,-5.1,-5.8;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
59h
71nO
15si, 1062; Measured value: 1062.
Embodiment 26: compound 26 synthetic
In 25mL round-bottomed flask, add successively 300mg (0.28mmol) compound 25,5.0mL tetrahydrofuran (THF) and tetrabutyl ammonium fluoride (0.56mL * 1.0M), at room temperature, stir 2 hours.React complete, be spin-dried for, cross silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～60%) obtain 252mg compound 26.Productive rate: 95%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.01 (d, 2H, J=7.2Hz), 7.65 (d, 2H, J=7.2Hz), 7.51 (t, 2H, J=7.2Hz), 7.41 (m, 5H), 7.30 (m, 4H), 7.24 (t, 1H, J=7.2Hz), 7.00 (d, 1H, J=7.8Hz), 6.12 (s, 2H), 6.06 (t, 1H, J=7.2Hz), 5.56 (d, 1H, J=7.2Hz), 5.52 (dd, 1H, J=9.0, 7.2Hz), 4.83 (d, 1H, J=9.0Hz), 4.69 (s, 1H), 4.22 (d, 1H, J=9.0Hz), 4.08 (d, 1H, J=9.0Hz), 3.81 (d, 1H, J=7.2Hz), 2.51 (m, 1H), 2.35 (m, 1H), 2.31 (m, 1H), 2.29 (s, 3H), 2.21 (m, 4H), 2.15 (m, 2H), 2.02 (s, 3H), 1.96 (s, 1H), 1.78 (m, 2H), 1.72 (s, 3H), 1.69 (s, 3H), 1.09 (s, 3H), 1.06 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ202.0,172.4,172.3,172.2,172.0,170.4,169.0,167.1,167.0,140.3,138.0,133.8,133.6,132.0,131.8,130.2,129.7,129.0,128.7,128.1,127.1,83.9,83.7,81.5,78.5,76.5,75.2,74.3,73.2,72.2,71.3,68.9,56.2,54.9,53.5,46.9,43.2,36.5,33.5,32.9,26.5,23.2,22.6,20.9,17.8,14.7,10.8;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
53h
57nO
15, 948; Measured value: 948.
Embodiment 27: compound 27 synthetic
In 10mL round-bottomed flask, add successively 35mg (0.04mmol) compound 26,50mg (0.32mmol) 6-azido--n-caproic acid, 2.0mL methyl alcohol, copper-bath (30uL * 1.0M) and sodium ascorbate salts solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: chloroform: methyl alcohol/0～10%) purifying obtains 37mg compound 27.Productive rate: 91%.
Nmr analysis:
1h NMR (500MHz, CD
3oD): δ 8.10 (d, 2H, J=7.2Hz), 7.87 (d, 2H, J=7.2Hz), 7.74 (s, 1H), 7.67 (t, 1H, J=7.2Hz), 7.35-7.68 (m, 9H), 7.30 (t, 1H, J=7.2Hz), 6.25 (s, 2H), 6.15 (t, 1H, J=7.2Hz), 5.64 (s, 1H), 5.58 (t, 1H, J=7.8Hz), 4.98 (d, 1H, J=9.0Hz), 4.78 (d, 1H, J=9.0Hz), 4.37 (t, 2H, J=7.2Hz), 4.22 (dd, 2H, J=9.0, 18.0Hz), 3.91 (d, 1H, J=7.2Hz), 3.12 (t, 2H, J=7.2Hz), 2.87 (t, 2H, J=7.2Hz), 2.51 (m, 1H), 2.35 (s, 3H), 2.28 (m, 4H), 2.15 (s, 3H), 2.05 (m, 7H), 1.96 (s, 3H), 1.65 (m, 3H), 1.35 (m, 2H), 1.16 (s, 3H), 1.12 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ202.3,177.1,173.1,172.4,170.5,169.2,168.9,166.2,147.0,140.6,138.5,134.1,133.3,132.9,131.5,129.8,128.4,128.3,128.2,127.6,127.1,121.9,83.8,80.5,77.5,75.9,75.2,74.4,73.3,71.4,70.7,56.4,55.8,49.8,46.1,43.2,35.0,33.0,29.7,25.9,25.4,24.8,23.8,22.3,21.9,21.8,21.4,20.7,19.5,13.4,10.1;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
59h
68n
4o
17, 1105; Measured value: 1105.
Embodiment 28: compound 28 synthetic
In 50mL round-bottomed flask, add successively 107mg (0.53mmol) 2-[2-oxygen-(4-alkynes amylamine base) oxyethyl group] acetic acid, 102mg (0.53mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stir 30 minutes.Then add 200mg (0.21mmol) compound 21 and 65mg (0.53mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 3) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: chloroform: methyl alcohol/0～5%) obtain 176mg compound 28.Productive rate: 75%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.02 (d, 2H, J=7.2Hz), 7.66 (d, 2H, J=7.2Hz), 7.51 (t, 1H, J=7.2Hz), 7.20 – 7.42 (m, 10H), 6.81 (d, 1H, J=7.8Hz), 6.78 (brs, 1H), 6.32 (s, 1H), 6.12 (t, 1H, J=9.0Hz), 5.92 (d, 1H, J=6.0Hz), 5.95 (m, 1H), 5.58 (d, 1H, J=7.2Hz), 5.54 (d, 1H, J=2.4Hz), 5.42 (t, 1H, J=9.0Hz), 5.23 (d, 1H, J=12.0Hz), 5.13 (d, 1H, J=9.0Hz), 4.88 (d, 1H, J=12.0Hz), 4.61 (m, 1H), 4.54 (m, 1H), 4.22 (d, 1H, J=7.2Hz), 4.07 (m, 3H), 3.97 (s, 1H), 3.89 (d, 1H, J=7.2Hz), 3.82 (d, 1H, J=7.2Hz), 3.30 (m, 2H), 2.55 (m, 1H), 2.39 (s, 3H), 2.28 (m, 1H), 2.15 (m, 4H), 2.05 (s, 3H), 1.95 (s, 3H), 1.94 (m, 2H), 1.78 (s, 3H), 1.65 (m, 1H), 1.17 (s, 3H), 1.05 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.7,170.6,169.9,169.8,168.6,167.8,167.6,167.1,154.0,140.7,136.7,133.7,133.4,132.8,132.1,131.7,130.2,129.7,129.2,128.8,128.7,128.6,128.1,127.1,126.3,118.8,83.9,83.2,80.8,78.7,76.4,75.3,75.2,74.5,72.2,71.3,71.2,69.4,69.1,68.1,56.1,52.6,47.0,43.2,38.1,35.4,33.4,28.1,26.5,22.6,21.1,20.7,16.1,13.4,10.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
60h
66n
2o
19, 1120; Measured value: 1120.
Embodiment 29: compound 29 synthetic
In 25mL round-bottomed flask, add successively 120mg (0.11mmol) compound 28,6mg (0.006mmol) tetrakis triphenylphosphine palladium, 26mg (0.16mmol) 1,3-dimethyl barbituric acid, 5.0mL anhydrous tetrahydro furan, then at room temperature stirs 2 hours.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: chloroform: methyl alcohol/0～8%) purifying obtains 101mg compound 29.Productive rate: 89%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.06 (d, 2H, J=7.2Hz), 7.62 (d, 2H, J=7.2Hz), 7.51 (t, 1H, J=7.2Hz), 7.20 – 7.43 (m, 10H), 6.77 (m, 2H), 6.20 (s, 1H), 6.17 (t, 1H, J=9.0Hz), 5.94 (d, 1H, J=6.0Hz), 5.85 (d, 1H, J=7.2Hz), 5.51 (s, 1H), 5.42 (t, 1H, J=9.0Hz), 4.88 (d, 1H, J=12.0Hz), 4.36 (t, 1H, J=7.2Hz), 4.23 (m, 1H), 4.10 (m, 1H), 4.03 (dd, 1H, J=12.0, 7.2Hz), 3.90 (m, 2H), 3.71 (d, 1H, J=7.2Hz), 3.28 (dd, 2H, J=12.0, 7.2Hz), 2.49 (m, 1H), 2.39 (s, 3H), 2.28 (m, 1H), 2.05 (s, 3H), 1.91 (m, 3H), 1.84 (m, 3H), 1.79 (t, 1H, J=12.0Hz), 1.70 (m, 3H), 1.62 (s, 3H), 1.17 (s, 3H), 1.05 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ203.7,171.3,169.8,169.1,168.5,167.6,167.2,167.1,142.5,136.5,133.7,133.5,133.0,132.2,130.3,129.3,128.8,128.7,126.5,126.4,84.5,83.1,81.1,79.2,76.4,75.5,75.1,74.6,72.2,72.1,71.2,69.4,58.7,52.6,45.6,43.2,38.1,35.6,28.0,26.8,22.7,22.1,20.9,16.1,14.8,9.6;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
56h
62n2O
17, 1035; Measured value: 1035.
Embodiment 30: compound 30 synthetic
In 10mL round-bottomed flask, add successively 35mg (0.03mmol) compound 29,50mg (0.32mmol) 6-azido--n-caproic acid, 2.0mL methyl alcohol, copper-bath (30uL * 1.0M) and sodium ascorbate salts solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: chloroform: methyl alcohol/0～10%) purifying obtains 30mg compound 30.Productive rate: 85%.
Nmr analysis:
1h NMR (500MHz, DMSO-D
6): δ 8.09 (d, 2H, J=7.2Hz), 7.78 (d, 2H, J=7.2Hz), 7.72 (s, 1H), 7.64 (t, 1H, J=7.2Hz), 7.55 (t, 2H, J=7.2Hz), 7.30-7.45 (m, 8H), 7.25 (t, 1H, J=7.2Hz), 6.42 (s, 1H), 6.05 (t, 1H, J=7.8Hz), 5.84 (d, 1H, J=6.0Hz), 5.61 (d, 1H, J=7.2Hz), 5.56 (d, 1H, J=7.2Hz), 5.21 (d, 1H, J=9.0Hz), 4.96 (d, 1H, J=9.0Hz), 4.65 (s, 1H), 4.46 (s, 1H), 4.33 (m, 4H), 4.20 (m, 2H), 4.15 (s, 2H), 4.00 (m, 3H), 3.78 (d, 1H, J=7.2Hz), 3.23 (t, 2H, J=7.2Hz), 2.68 (t, 2H, J=7.2Hz), 2.42 (m, 2H), 2.37 (s, 3H), 2.25 (m, 3H), 2.17 (m, 1H), 2.13 (s, 3H), 1.96 (s, 3H), 1.83 (m, 3H), 1.75 (t, 1H, J=12.0Hz), 1.62 (s, 3H), 1.57 (m, 4H), 1.27 (m, 2H), 1.11 (s, 3H), 1.09 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ203.7,175.8,170.5,170.0,169.8,169.1,168.5,166.3,146.9,140.7,138.6,134.2,133.5,131.6,132.0,129.8,128.7,128.6,128.4,127.2,127.1,122.0,84.5,81.7,77.5,75.6,74.8,73.2,72.7,71.8,70.8,70.1,57.8,53.7,50.3,46.5,43.2,38.5,36.1,33.2,29.3,26.2,24.8,22.6,21.7,20.8,19.3,13.6,9.1;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
62h
73n5O
19, 1092; Measured value: 1092.
Embodiment 31: covalent polymer 31 synthetic
In 10mL round-bottomed flask, by 1.0g dextran (molecular-weight average is～7000), 200mg N, N'-carbonyl dimidazoles, 100mg6-azido-n-caproic acid and 200uL triethylamine are dissolved in 5.0mL dimethyl sulfoxide (DMSO), at room temperature stir 12 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times, obtains 0.98g covalent polymer 31.
Embodiment 32: covalent polymer 32 synthetic
In 5mL round-bottomed flask, add successively 100mg covalent polymer 31,20mg (0.021mmol) compound 301.0mL dimethyl sulfoxide (DMSO), copper-bath (30uL * 1.0M) and sodium ascorbate salts solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 82mg product.This product absorbs at 280nm ultraviolet wavelength by control compound 30, measures content of taxol 15% (w/w).
Embodiment 33: covalent polymer 33 synthetic
In 5mL round-bottomed flask, add successively 100mg covalent polymer 31,20mg (0.021mmol) compound 27,1.0mL dimethyl sulfoxide (DMSO), copper-bath (30uL * 1.0M) and sodium ascorbate salts solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 78mg product.This product absorbs at 280nm ultraviolet wavelength by control compound 27, measures content of taxol 12% (w/w).
Embodiment 34: covalent polymer 34 synthetic
In 5mL round-bottomed flask, add successively 100mg covalent polymer 31,20mg (0.021mmol) compound 24,1.0mL dimethyl sulfoxide (DMSO), copper-bath (30uL * 1.0M) and sodium ascorbate salts solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 89mg product.This product absorbs at 280nm ultraviolet wavelength by control compound 27, measures content of taxol 16% (w/w).
Synthetic route 6
Reaction conditions and reagent:
A) knot propylhomoserin methyl ester hydrochloride/N, N'-carbonyl dimidazoles/triethylamine/dimethyl sulfoxide (DMSO), room temperature, 12h;
B) 1.0M sodium hydroxide, 12h; 1.0M hydrochloric acid, pH=5.0;
C) compound 5/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/I-hydroxybenzotriazole (HOBt)/DIPEA, dimethyl sulfoxide (DMSO), room temperature, 2h.
Embodiment 35: covalent polymer 35 synthetic
In 5mL round-bottomed flask, by 500mg dextran (molecular-weight average is～15,000), 100mg N, N'-carbonyl dimidazoles, 100mg knot propylhomoserin methyl ester hydrochloride and 200uL triethylamine are dissolved in 5.0mL dimethyl sulfoxide (DMSO), at room temperature stir 12 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out be dissolved in 5.0mL distilled water and add 300mg sodium hydroxide, at room temperature stirring 12 hours, then using in 1.0N dilute hydrochloric acid and PH=5.0.Reaction mixture is through dialysis, and lyophilize, obtains 325mg covalent polymer 35.
Embodiment 36: covalent polymer 36 synthetic
In 5mL round-bottomed flask, by 100mg covalent polymer 35,20mg (0.019mmol) compound 5,30mg (0.15mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC), 25mg (0.18mmol) I-hydroxybenzotriazole (HOBt) and 200uL N, N-diisopropylethylamine is dissolved in 1.5mL dimethyl sulfoxide (DMSO), at room temperature stirs 2 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 73mg covalent polymer 36.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures Docetaxel content 15% (w/w).
Synthetic route 7
Reaction conditions and reagent:
A) sodium methylate/di-alcohol acid anhydrides, anhydrous tetrahydro furan ,-20 ℃, 6h;
B) compound 8 or compound 25/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
C) tetrakis triphenylphosphine palladium/1,3-dimethyl barbituric acid, tetrahydrofuran (THF), room temperature, 2h;
D) 4-diazabicylo [2.2.2] octane/polysaccharide covalent body 31, dimethyl sulfoxide (DMSO), 40 ℃, 6h.
Embodiment 37: compound 37 synthetic
Under nitrogen protection, in 100mL round-bottomed flask, add successively 1.0g (3.47mmol) the acetylthio methyldiphenyl base borane mixture of seeing; 10.0mL anhydrous tetrahydro furan; be cooled to-20 ℃, then add 206mg (3.87mmol) sodium methylate, stir 1 hour.Then, add 635mg (5.67mmol) di-alcohol acid anhydrides.React complete, be spin-dried for, reaction mixture, in 5% Citric Acid (100mL) and ethyl acetate (100mL), is isolated ethyl acetate layer, further uses 5% Citric Acid (100mL * 2).Be spin-dried for, through silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～60%) purifying obtains 1.26g compound 37.Productive rate: 95%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 7.67 (m, 4H), 7.49 (m, 2H), 7.45 (m, 4H0,4.17 (s, 2H), 4.05 (s, 2H), 3.68 (d, 2H, J=6.0Hz), 2.90 (brs, 3H);
13C?NMR(75MHz,CDCl
3):δ197.1,171.3,132.5,132.4,128.8,127.5,127.1,75.3,68.4,22.4;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
17h
20bO
4pS, 362; Measured value: 362.
Embodiment 38: compound 38 synthetic
In 25mL round-bottomed flask, add successively 231mg (0.64mmol) compound 37,122mg (0.64mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 5.0mL anhydrous chloroform, at room temperature, stirs 30 minutes.Then add 200mg (0.21mmol) compound 8 and 78mg (0.64mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～70%) obtain 272mg compound 38.Productive rate: 98%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.13 (d, 2H, J=7.2Hz), 7.31 (m, 5H), 7.61 (t, 1H, J=7.2Hz), 7.47 – 7.53 (m, 10H), 7.39 (m, 2H), 7.34 (m, 1H), 6.24 (brs, 2H), 5.97 (m, 2H), 5.70 (d, 1H, J=6.0Hz), 5.52 (brs, 1H), 5.31 – 5.42 (m, 4H), 5.25 (d, 1H, J=12.0Hz), 4.99 (d, 1H, J=9.0Hz), 4.65 (m, 2H), 4.35 (d, 1H, J=9.0Hz), 4.25 (s, 1H), 4.18 (d, 1H, J=9.0Hz), 4.12 (m, 6H), 3.95 (m, 1H), 3.73 (t, 2H, J=7.2Hz), 2.63 (m, 1H), 2.49 (s, 3H), 2.36 (m, 1H), 2.26 (m, 1H), 2.15 (s, 3H), 2.00 (t, 1H, J=12.0Hz), 1.84 (s, 3H), 1.35 (s, 9H), 1.25 (s, 3H), 1.19 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.7,196.7,196.3,171.3,169.7,168.4,167.7,166.9,155.7,153.9,153.7,142.5,136.7,133.7,132.5,132.4,131.9,131.4,130.1,129.0,128.9,128.8,128.7,128.3,126.2,119.2,118.7,83.8,80.7,78.7,78.1,76.3,75.4,75.2,74.8,74.4,72.0,69.1,68.8,68.3,68.1,56.0,53.6,46.8,43.1,35.0,33.3,28.1,26.2,22.6,22.5,21.2,14.6,10.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
17h
20bO
4pS, 1320; Measured value: 1320.
Embodiment 39: compound 39 synthetic
In 25mL round-bottomed flask, add successively 231mg (0.64mmol) compound 37,122mg (0.64mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 5.0mL anhydrous chloroform, at room temperature, stirs 30 minutes.Then add 200mg (0.21mmol) compound 21 and 78mg (0.64mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～70%) obtain 251mg compound 39.Productive rate: 93%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.13 (d, 2H, J=7.2Hz), 7.35 (m, 7H), 7.62 (t, 1H, J=7.2Hz), 7.27 – 7.54 (m, 15H), 6.93 (d, 1H, J=9.0Hz), 6.40 (s, 1H), 6.25 (t, 1H, J=9.0Hz), 6.02 (d, 1H, J=7.8Hz), 5.97 (m, 1H), 5.71 (d, 1H, J=7.8Hz), 5.60 (s, 1H), 5.53 (t, 1H, J=7.2Hz), 5.35 (d, 1H, J=17.4Hz), 5.31 (s, 1H), 5.25 (d, 1H, J=12.0Hz), 5.00 (d, 1H, J=9.0Hz), 4.72 (m, 1H), 4.67 (m, 1H), 4.34 (d, 1H, J=9.0Hz), 4.20 (m, 4H), 4.13 (m, 3H), 4.06 (s, 2H), 3.96 (d, 1H, J=6.6Hz), 3.73 (d, 2H, J=7.2Hz), 3.67 (m, 1H), 3.62 (m, 1H), 2.65 (m, 1H), 2.47 (s, 3H), 2.41 (m, 1H), 2.24 (m, 1H), 2.17 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 1.97 (m, 1H), 1.85 (m, 1H), 1.83 (s, 3H), 1.23 (s, 3H), 1.18 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.7,196.5,196.2,169.6,169.8,168.4,167.6,167.4,166.8,153.9,140.9,136.4,133.7,133.2,132.5,132.4,132.1,131.8,130.2,129.2,129.0,128.9,128.8,128.7,128.6,127.0,126.4,118.8,83.9,80.8,78.6,76.3,75.4,75.3,75.2,74.4,72.1,69.1,68.3,68.2,56.0,53.4,46.9,43.2,35.3,33.3,26.4,22.6,22.5,22.3,21.3,20.7,14.5,10.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
68h
73bNO
19pS, 1282; Measured value: 1282.
Embodiment 40: compound 40 synthetic
In 25mL round-bottomed flask, add successively 200mg (0.15mmol) compound 38,17mg (0.02mmol) tetrakis triphenylphosphine palladium, 59mg (0.37mmol) 1,3-dimethyl barbituric acid, 5.0mL anhydrous tetrahydro furan, then at room temperature stirs 2 hours.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～70%) purifying obtains 146mg compound 40.Productive rate: 85%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.13 (d, 2H, J=7.2Hz), 7.72 (t, 3H, J=7.2Hz), 7.62 (t, 1H, J=7.2Hz), 7.28 – 7.52 (m, 14H), 6.25 (s, 1H), 5.70 (d, 1H, J=7.2Hz), 5.51 (brs, 1H), 5.45 (s, 1H), 5.38 (d, 1H, J=9.0Hz), 5.31 (s, 1H), 5.23 (s, 1H), 4.97 (d, 1H, J=9.0Hz), 4.33 (d, 1H, J=9.0Hz), 4.33 (d, 1H, J=7.2Hz), 4.20 (m, 3H), 4.11 (s, 4H), 3.94 (d, 1H, J=7.0Hz), 3.72 (d, 1H, J=7.0Hz), 2.61 (m, 1H), 2.45 (s, 3H), 2.35 (m, 1H), 2.21 (m, 1H), 2.06 (s, 3H), 1.95 (s, 3H), 1.85 (t, 1H, J=12.0Hz), 1.77 (s, 3H), 1.34 (s, 9H), 1.25 (s, 3H), 1.14 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ211.5,196.3,169.7,168.5,167.5,167.0,155.0,138.3,135.6,133.7,132.5,132.4,131.9,130.2,129.1,129.0,128.9,128.7,128.3,127.6,127.2,126.1,84.1,80.9,78.1,76.5,75.3,74.9,74.8,74.5,72.3,71.8,68.1,57.5,53.9,46.4,43.1,36.9,35.5,28.1,26.3,22.6,22.5,22.3,20.8,14.2,9.9;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
60h
71bNO
17pS, 1152; Measured value: 1152.
Embodiment 41: compound 41 synthetic
In 25mL round-bottomed flask, add successively 200mg (0.16mmol) compound 39,10mg (0.008mmol) tetrakis triphenylphosphine palladium, 32mg (0.21mmol) 1,3-dimethyl barbituric acid, 5.0mL anhydrous tetrahydro furan, then at room temperature stirs 2 hours.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～60%) purifying obtains 169mg compound 41.Productive rate: 89%
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.16 (d, 2H, J=7.2Hz), 7.73 (d, 2H, J=7.2Hz), 7.68 (t, 4H, J=7.2Hz), 7.62 (t, 1H, J=7.2Hz), 7.53 (m, 5H), 7.30 – 7.45 (m, 11H), 6.88 (d, 1H, J=9.0Hz), 6.31 (s, 1H), 6.27 (t, 1H, J=9.0Hz), 6.03 (d, 1H, J=7.8Hz), 5.70 (d, 1H, J=7.2Hz), 5.58 (s, 1H), 5.00 (d, 1H, J=9.0Hz), 4.46 (brs, 1H), 4.34 (d, 1H, J=9.0Hz), 4.21 (m, 3H), 4.12 (m, 3H), 3.82 (d, 1H, J=7.2Hz), 3.65 (m, 2H), 2.60 (m, 1H), 2.56 (m, 1H), 2.48 (s, 3H), 2.39 (m, 1H), 2.24 (s, 3H), 2.19 (m, 1H), 2.06 (s, 1H), 1.95 (s, 3H), 1.88 (t, 1H, J=12.0Hz), 1.25 (s, 3H), 1.15 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ203.8,196.2,171.3,169.8,168.5,167.5,167.0,142.5,136.5,133.7,133.4,132.4,132.3,132.1,131.8,130.2,129.2,129.1,128.9,128.8,128.7,128.6,127.1,126.4,84.4,81.0,79.1,76.4,75.5,75.3,74.6,73.9,72.1,68.2,56.5,52.6,45.5,43.1,35.5,31.8,26.8,22.6,22.2,20.3,14.1,9.6;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
64h
69bNO
17pS, 1198; Measured value: 1198.
Embodiment 42: covalent polymer 42 synthetic
In 5mL round-bottomed flask, by 100mg covalent polymer 31,20mg (0.019mmol) compound 40,20mg4-diazabicylo [2.2.2] octane is dissolved in 1.5mL dimethyl sulfoxide (DMSO), is heated to 40 ℃ and stirs 4 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 92mg covalent polymer 42.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures Docetaxel content 23% (w/w).
Embodiment 43: covalent polymer 43 synthetic
In 5mL round-bottomed flask, by 100mg covalent polymer 31,20mg (0.019mmol) compound 41,20mg4-diazabicylo [2.2.2] octane is dissolved in 1.5mL dimethyl sulfoxide (DMSO), is heated to 40 ℃ and stirs 4 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 83mg covalent polymer 43.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures Docetaxel content 25% (w/w).
Synthetic route 8
Reaction conditions and reagent:
A) the amino n-caproic acid of cyanogen bromide/sodium bicarbonate/6-, PH=10, water, room temperature, 24h;
B) compound 5/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/I-hydroxybenzotriazole (HOBt)/DIPEA, dimethyl sulfoxide (DMSO), room temperature, 2h.
Embodiment 44: covalent polymer 44 synthetic
In 25mL round-bottomed flask, 500mg dextran (molecular-weight average is～7000) is dissolved in to 5.0mL distilled water, then add 200mg cyanogen bromide, and sodium bicarbonate adjusting PH=10, then add the amino n-caproic acid of 200mg6-, at room temperature stir 24 hours.React complete, reaction mixture regulates PH=3.0 with 1N dilute hydrochloric acid, then filters, and dialysis, obtains covalent polymer 44 (327mg) through lyophilize.
Embodiment 45: covalent polymer 45 synthetic
In 5mL round-bottomed flask, by 100mg covalent polymer 44,20mg (0.019mmol) compound 5,30mg (0.15mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC), 25mg (0.18mmol) I-hydroxybenzotriazole (HOBt) and 200uL N, N-diisopropylethylamine is dissolved in 1.5mL dimethyl sulfoxide (DMSO), at room temperature stirs 2 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 83mg covalent polymer 45.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures Docetaxel content 9.8% (w/w).
Synthetic route 9
Reaction conditions and reagent:
A) di-alcohol acid anhydrides/triethylamine, anhydrous tetrahydro furan, room temperature, 12h;
B) N, N'-carbonyl dimidazoles/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h; C) hydrogen/palladium-carbon, room temperature, 2h.
Embodiment 46: compound 46 synthetic
In 25mL round-bottomed flask, 300mg (0.307mmol) compound 8 is dissolved in to 5.0mL anhydrous tetrahydro furan, then add 100mg (0.893mmol) di-alcohol acid anhydrides 1.0mL (7.18mmol) triethylamine, at room temperature stir 12 hours.React complete, after being spin-dried for, in ethyl acetate (50mL) and 10% citric acid soln (50mL), distribute, isolate organic phase, then with 10% 2 times (50mL * 2) of citric acid soln washing, be spin-dried for, through silica gel column chromatography (eluent: ethyl acetate: sherwood oil/20～70%) purifying obtains 217mg compound 46.Productive rate: 65%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.11 (d, 2H, J=7.2Hz), 7.62 (t, 1H, J=7.2Hz), 7.51 (t, 2H, J=7.2Hz), 7.31 (m, 3H), 6.18 (s, 2H), 5.99 (m, 2H), 5.67 (s, 1H), 5.20-5.51 (m, 6H), 4.99 (d, 1H, J=7.2Hz), 4.67 (m, 6H), 4.31 (m, 1H), 4.17 (m, 2H), 4.11 (m, 2H), 3.90 (m, 4H), 2.61 (m, 1H), 2.49 (s, 3H), 2.31 (m, 1H), 2.10 (m, 1H), 1.96 (s, 3H), 1.83 (s, 3H), 1.29 (s, 9H), 1.19 (s, 3H), 1.16 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.6,175.7,170.2,169.7,168.2,166.9,155.5,154.0,153.8,141.9,137.0,133.7,132.3,131.7,131.4,130.1,128.9,128.7,128.4,126.8,126.6,119.2,118.8,83.8,80.7,80.2,78.7,78.1,76.3,75.3,75.1,74.3,72.0,69.2,68.9,56.0,54.0,46.8,43.0,35.0,33.2,28.1,26.2,22.4,21.0,14.6,10.6;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
55h
66nO
22, 1092; Measured value: 1092.
Embodiment 47: covalent polymer 47 synthetic
In 5mL round-bottomed flask, by 50mg (0.308mmol) N, N'-carbonyl dimidazoles, 50mg (0.046mmol) compound 46 is dissolved in 3.0mL dimethyl sulfoxide (DMSO), at room temperature stir 30 minutes, 300mg dextran (molecular-weight average is～30,000) and 0.5mL triethylamine, continue to stir 12 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times, and lyophilize, obtains 320mg product.
Embodiment 48: covalent polymer 48 synthetic
In 50mL round-bottomed flask, 320mg covalent polymer 47 is dissolved in 10.0mL20% methanol aqueous solution, and adds palladium-carbon of 50mg, at room temperature pass into hydrogen 12 hours.React complete, filter, put into bag generation dialysis.Dialyse complete, through lyophilize, obtain 283mg covalent polymer 48.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures Docetaxel content 11% (w/w).
Synthetic route 10
Reaction conditions and reagent:
A) N, N'-carbonyl dimidazoles/N'-fluorenes methoxy carbonyl acyl group methyllysine hydrochloride/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h; Piperidines, dimethyl sulfoxide (DMSO), room temperature, 12h;
B) hydrogen/palladium-carbon, methyl alcohol, room temperature, 12h;
C) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/I-hydroxybenzotriazole (HOBt)/DIPEA, dimethyl sulfoxide (DMSO), room temperature, 2h.
Embodiment 49: covalent polymer 49 synthetic
In 5mL round-bottomed flask, 300mg (0.717mmol) N'-fluorenes methoxy carbonyl acyl group methyllysine hydrochloride and 1.0mL (5.67mmol) triethylamine are dissolved in 2.0mL dimethyl sulfoxide (DMSO), 50 ℃ of heating 30 minutes.In addition, in 5mL round-bottomed flask, add 500mg dextran (molecular-weight average is～15,000) and 100mg (0.641mmol) N, N'-carbonyl dimidazoles, was dissolved in 3.0mL dimethyl sulfoxide (DMSO), stirring at room 30 minutes.Then above-mentioned two kinds of solution are mixed, continue to stir 12 hours.Reaction mixture methanol extraction, filters, and uses methanol wash 3 times, is then dissolved in 5.0mL dimethyl sulfoxide (DMSO), and adds 2.0mL piperidines, at room temperature stirs 2 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times, and lyophilize, obtains 560mg covalent polymer 49.
Embodiment 50: compound 50 synthetic
In 50mL round-bottomed flask, 300mg (0.275mmol) compound 46 is dissolved in 10.0mL methanol aqueous solution, and adds palladium-carbon of 50mg, at room temperature pass into hydrogen 2 hours.React complete, filter, on anti-phase C-18 post through high performance liquid chromatography (eluent: methyl alcohol: water/30～90%), obtain 231mg compound 50, productive rate 90%.
Nmr analysis:
1h NMR (500MHz, CD
3oD): δ 8.09 (d, 2H, J=7.2Hz), 7.62 (t, 1H, J=7.2Hz), 7.53 (t, 2H, J=7.2Hz), 7.36 (m, 4H), 7.22 (m, 1H), 6.08 (s, 2H), 5.60 (t, 1H, J=7.2Hz), 5.31 (t, 1H, J=13.8Hz), 5.29 (s, 1H), 4.96 (d, 1H, J=13.8Hz), 4.87 (m, 2H), 4.56 (m, 2H), 4.27 (m, 2H), 4.17 (m, 1H), 4.12 (s, 2H), 3.84 (s, 2H), 3.81 (m, 2H), 2.43 (m, 1H), 2.38 (s, 3H), 1.96 (m, 1H), 1.85 (s, 3H), 1.78 (t, 1H, J=12.1Hz), 1.45 (s, 3H), 1.36 (s, 9H), 1.13 (s, 3H), 1.09 (s, 3H),
13C?NMR(125MHz,CD
3OD):δ211.3,177.0,171.9,171.8,170.0,167.8,158.0,139.6,139.0,138.0,134.4,131.5,131.4,130.0,129.8,129.7,129.5,128.3,86.1,82.4,80.8,79.1,77.7,76.7,76.5,75.8,73.6,72.7,71.4,68.4,58.9,56.3,48.1,44.6,37.9,36.8,28.4,27.1,23.3,21.7,14.6,9.4;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
47h
58nO
18, 924; Measured value: 924.
Embodiment 51: covalent polymer 51 synthetic
In 5mL round-bottomed flask, by 50mg(0.052mmol) compound 50,20mg (0.105mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 50mg (0.370mmol) I-hydroxybenzotriazole (HOBt) are dissolved in 3.0mL dimethyl sulfoxide (DMSO), stir 30 minutes.Then add 300mg covalent polymer 49 and 200uL DIPEA, at room temperature react 2 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 283mg covalent polymer 51.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures Docetaxel content 9% (w/w).
Synthetic route 11
Reaction conditions and reagent:
A) allyl group diethyl alkyd list acid esters/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/I-hydroxybenzotriazole (HOBt)/DIPEA, DMF, room temperature, room temperature, 6h;
B) trichloromethyl carbonochloridic acid ester/DIPEA/compound 8, chloroform, 0 ℃, 2h;
C) two (triphenylphosphine) palladium chloride/acetic acid/tributyl tin hydrogen, chloroform, room temperature, 2h;
D) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/I-hydroxybenzotriazole (HOBt)/DIPEA, dimethyl sulfoxide (DMSO), room temperature, 2h.
Embodiment 52: compound 52 synthetic
In 50mL round-bottomed flask, by 500mg (2.87mmol) allyl group diethyl alkyd list acid esters, 660mg (3.45mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 465mg (3.45mmol) I-hydroxybenzotriazole (HOBt) are dissolved in 10.0mL N, in dinethylformamide, stir 30 minutes.Then add 317mg (2.58mmol) to aminobenzyl alcohol and 2mL DIPEA, at room temperature react 6 hours.React complete, reaction mixture distributes in ethyl acetate and saturated nacl aqueous solution, isolates organic phase, with saturated sodium-chloride washing 2 times, is spin-dried for, through silica gel column chromatography (eluent: chloroform: methyl alcohol/1～10%) purifying obtains 375mg compound 52.Productive rate: 52%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.23 (s, 1H), 7.51 (d, 2H, J=7.8Hz); 7.23 (d, 2H, J=7.8Hz), 5.85 (m; 1H), 5.26 (d, 1H, J=16.8Hz); 5.20 (d, 1H, J=9.8Hz), 4.61 (d; 2H, J=7.0Hz), 4.56 (s, 2H); 4.18 (s, 1H), 4.10 (s, 2H);
13C?NMR(75MHz,CDCl
3):δ170.0,168.0,137.1,136.7,131.2,128.0,120.0,119.6,71.9,69.2,66.2,65.0;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
14h
18nO
5, 280; Measured value: 280.
Embodiment 53: compound 53 synthetic
In 25mL round-bottomed flask; under argon shield, 100mg (0.358mmol) compound 52 is dissolved in to 5.0mL anhydrous chloroform; be cooled to 0 ℃; then add successively 30uL (0.251mmol) trichloromethyl carbonochloridic acid ester and 500uL (2.83mmol) N; N-diisopropylethylamine, stirs 1 hour.Be spin-dried for, reaction mixture under argon shield, is dissolved in 5.0mL anhydrous chloroform again; then add 200mg (0.205mmol) compound 8; trichloromethyl carbonochloridic acid ester and 500uL (2.83mmol) and DIPEA (300uL), continue to stir 12 hours.React complete, reaction mixture distributes in ethyl acetate and saturated nacl aqueous solution, isolates organic phase, with saturated sodium-chloride washing 2 times, be spin-dried for, through silica gel column chromatography (eluent: ethyl acetate: sherwood oil/20～80%) purifying obtains 171mg compound 53, productive rate: 65%.
Nmr analysis:
1h NMR (500MHz, CDCl
3): δ 8.87 (s, 1H), 8.02 (d, 2H, J=7.2Hz), 7.53 (m3H), 7.41 (t, 2H, J=7.2Hz), 7.31 (t, 2H, J=7.2Hz), 7.21 (m, 5H), 6.15 (s, 1H), 5.83 (m, 3H), 5.60 (d, 1H, J=7.0Hz), 5.42 (m, 1H), 5.10-5.35 (m, 6H), 5.02 (m, 2H), 4.86 (d, 1H, J=9.0Hz), 4.61 (d, 1H, J=7.0Hz), 4.53 (m, 4H), 4.25 (d, 1H, J=8.4Hz), 4.20 (s, 2H), 4.10 (s, 2H), 4.05 (m, 1H), 2.55 (m, 1H), 2.35 (s, 3H), 2.26 (m, 1H), 2.15 (m, 1H), 1.96 (s, 3H), 1.90 (t, 1H, J=12.6Hz), 1.68 (s, 3H), 1.24 (s, 9H), 1.19 (s, 3H), 1.16 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.9,170.0,169.7,168.1,167.1,167.0,155.2,154.0,153.9,153.8,142.5,138.0,137.1,133.1,132.1,132.0,131.5,131.1,130.4,130.2,129.5,129.1,129.0,128.8,128.3,126.5,120.0,119.6,119.2,118.8;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
66h
77n
2o
24, 1281; Measured value: 1281.
Embodiment 54: compound 54 synthetic
In 50mL round-bottomed flask, 150mg (0.117mmol) compound 53 is dissolved in 10.0mL methanol aqueous solution, and adds palladium-carbon of 50mg, at room temperature pass into hydrogen 2 hours.React complete, filter, on anti-phase C-18 post through high performance liquid chromatography (eluent: methyl alcohol: water/30～90%), obtain 95mg compound 54, productive rate: 75%.
Nmr analysis:
1h NMR (500MHz, CD
3oD): δ 8.01 (d, 2H, J=7.2Hz), 7.61 (d, 2H, J=7.2Hz), 7.53 (t, 1H, J=7.2Hz), 7.47 (t, 2H, J=7.2Hz), 7.28 (m, 4H), 7.16 (m, 1H), 5.98 (t, 1H, J=6.0Hz), 5.54 (d, 1H, J=7.0Hz), 5.19 (m, 2H), 5.14 (d, 1H, J=6.0Hz), 5.06 (m, 2H), 4.91 (d, 1H, J=9.8Hz), 4.16 (m, 1H), 4.09 (s, 2H), 4.04 (s, 2H), 3.93 (s, 2H), 3.76 (d, 1H, J=7.0Hz), 2.38 (m, 1H), 2.34 (s, 3H), 2.09 (m, 1H), 1.83 (m, 1H), 1.98 (s, 3H), 1.58 (s, 3H), 1.30 (s, 9H), 1.05 (s, 3H), 1.02 (s, 3H),
13C?NMR(125MHz,CD
3OD):δ209.8,176.3,170.2,169.8,168.9,167.2,166.3,156.4,155.4,138.4,138.1,137.3,136.5,133.2,130.0,129.8,128.9,128.6,128.3,128.0,126.9,120.0,84.6,80.8,79.5,77.8,77.2,76.2,75.0,74.3,72.0,71.2,71.1,70.8,69.7,57.5,55.1,46.2,43.4,36.3,35.2,28.1,26.2,21.3,20.7,13.2,9.1;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
55h
65n
2o
20, 1073; Measured value: 1073.
Embodiment 55: covalent polymer 55 synthetic
In 5mL round-bottomed flask, by 30mg (0.028mmol) compound 54,20mg (0.0104mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 50mg (0.307mmol) I-hydroxybenzotriazole (HOBt) are dissolved in 3.0mL dimethyl sulfoxide (DMSO), stir 30 minutes.Then add 300mg covalent polymer 49 and 200uL DIPEA, at room temperature react 2 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 283mg covalent polymer 55.This product absorbs at 280nm ultraviolet wavelength by control compound 54, measures Docetaxel content 2% (w/w).
Synthetic route 12
Reaction conditions and reagent:
A) compound 5/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/I-hydroxybenzotriazole (HOBt)/DIPEA, dimethyl sulfoxide (DMSO), room temperature, 2h;
B) compound 17/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/I-hydroxybenzotriazole (HOBt)/DIPEA, dimethyl sulfoxide (DMSO), room temperature, 2h;
C) 6-azido--n-caproic acid/N, N'-carbonyl dimidazoles/triethylamine/dimethyl sulfoxide (DMSO), room temperature, 12h; D) 6-azido--n-caproic acid/copper sulfate/vitamin C sodium salt, dimethyl sulfoxide (DMSO), room temperature, 12h.
Embodiment 56: covalent polymer 56 synthetic
In 5mL round-bottomed flask, by 100mg hyaluronic acid, (molecular-weight average is～12,000), 20mg (0.019mmol) compound 5,30mg (0.15mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC), 25mg (0.18mmol) I-hydroxybenzotriazole (HOBt) and 200uL DIPEA are dissolved in 1.5mL dimethyl sulfoxide (DMSO), at room temperature stir 2 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 83mg covalent polymer 56.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures Docetaxel content 25% (w/w).
Embodiment 57: covalent polymer 57 synthetic
In 5mL round-bottomed flask, by 150mg N, N'-carbonyl dimidazoles and 100mg6-azido-n-caproic acid are dissolved in 2.0mL dimethyl sulfoxide (DMSO), and (molecular-weight average is～12 then to add 300mg hyaluronic acid, 000) and 200uL triethylamine, at room temperature stir 12 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times, obtains covalent polymer 57 (235mg).
Embodiment 58: covalent polymer 58 synthetic
In 5mL round-bottomed flask, by 100mg hyaluronic acid, (molecular-weight average is～12,000), 20mg (0.019mmol) compound 17,30mg (0.15mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC), 25mg (0.18mmol) I-hydroxybenzotriazole (HOBt) and 200uL DIPEA are dissolved in 1.5mL dimethyl sulfoxide (DMSO), at room temperature stir 2 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 102mg covalent polymer 58.This product absorbs at 280nm ultraviolet wavelength by contrast Docetaxel, measures Docetaxel content 22% (w/w).
Embodiment 59: covalent polymer 59 synthetic
In 5mL round-bottomed flask, add successively 100mg covalent polymer 57,20mg (0.021mmol) compound 23,1.0mL dimethyl sulfoxide (DMSO), copper-bath (30uL * 1.0M) and sodium ascorbate salts solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 86mg covalent polymer 59.This product absorbs at 280nm ultraviolet wavelength by control compound 27, measures content of taxol 12% (w/w).
Synthetic route 13
Reaction conditions and reagent:
A) benzyl diglycollic acid monoesters/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
B) tetrakis triphenylphosphine palladium/1,3-dimethyl barbituric acid, chloroform, room temperature, 2h;
C) chlorotriethyl silane/imidazoles, dimethyl formamide, room temperature, 24h;
D) hydrogen/palladium-carbon, methyl alcohol, room temperature, 12h;
E) (i) N, N'-carbonyl dimidazoles/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h; (ii) tetrabutyl ammonium fluoride, dimethyl sulfoxide (DMSO), room temperature, 2h.
Embodiment 60: compound 60 synthetic
In 50mL round-bottomed flask, add successively 133mg (0.64mmol) benzyl diglycollic acid monoesters, 121mg (0.64mmol) N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stirs 30 minutes.Then add 300mg (0.32mmol) compound 21 and 78mg (0.64mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed three times (20mL * 3) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～70%) obtain 315mg compound 60.Productive rate: 86%.
Caryoplasm spectrum analysis:
1h NMR (500MHz, CDCl
3): δ 8.04 (d, J=7.8Hz, 2H), 7.68 (d, J=7.8Hz, 2H), 7.51 (t, J=7.8Hz, 2H), 7.39 (m, 3H), 7.21 – 7.23 (m, 12H), 6.29 (s, 1H), 6.14 (t, J=7.8Hz, 1H), 5.98 (d, J=10.2Hz, 1H), 5.19 (s, H), 5.15 (d, J=9.0Hz, 1H), 5.00 (m, 2H), 4.89 (d, J=9.0Hz, 1H), 4.62 (m, 1H), 4.56 (m, 1H), 4.24 (m, 3H), 4.11 (s, 2H), 4.03 (s, 4H), 3.99 (s, 2H), 3.87 (d, J=6.0Hz, 1H), 2.52 (m, 1H), 2.37 (s, 3H), 2.31 (m, 1H), 2.15 (m, 1H), 2.06 (s, 3H), 1.95 (s, 3H), 1.80 (m, 1H), 1.85 (s, 3H), 1.72 (s, 3H), 1.19 (s, 3H), 1.06 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.8,170.5,169.8,169.6,168.9,168.8,167.8,167.7,166.9,153.9,141.1,136.7,135.0,133.7,133.5,132.1,131.9,130.2,129.1,128.8,128.7,128.6,128.5,128.4,128.3,127.1,126.6,118.8,83.9,80.8,78.6,76.4,75.4,75.3,74.5,75.3,72.1,69.2,68.3,68.0,67.8,56.1,52.8,46.9,43.3,35.3,33.3,26.5,22.7,21.4,20.8,14.5,10.8;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
62h
65nO
20, 1144; Measured value: 1144.
Embodiment 61: compound 61 synthetic
In 25mL round-bottomed flask, add successively 300mg (0.26mmol) compound 60,11mg (0.01mmol) tetrakis triphenylphosphine palladium, 44mg (0.28mmol) 1,3-dimethyl barbituric acid, 5.0mL anhydrous tetrahydro furan, then at room temperature stirs 2 hours.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～70%) purifying obtains 247mg compound 61.Productive rate: 89%.
Caryoplasm spectrum analysis:
1h NMR (500MHz, CDCl
3): δ 8.16 (d, J=7.8Hz, 2H), 7.65 (d, J=7.8Hz, 2H), 7.51 (t, J=7.8Hz, 2H), 7.39 (m, 3H), 7.21 – 7.23 (m, 12H), 6.98 (d, J=9.0Hz, 1H), 6.19 (m, 2H), 5.98 (d, J=7.8Hz, 1H), 5.60 (d, J=7.2Hz, 1H), 5.49 (d, J=3.0Hz, 1H), 5.02 (dd, J=10.2, 7.8Hz, 2H), 4.89 (d, J=7.8Hz, 1H), 4.34 (m, 1H), 4.22 (m, 3H), 4.13 (m, 1H), 4.09 (s, 2H), 3.73 (d, J=6.0Hz, 1H), 2.48 (m, 1H), 2.39 (s, 3H), 2.31 (dd, J=15.0, 9.0Hz, 1H), 2.13 (s, 3H), 2.11 (dd, J=15.0, 9.0Hz, 1H), 1.84 (s, 3H), 1.79 (m, 1H), 1.59 (s, 3H), 1.15 (s, 3H), 1.05 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.8,171.3,169.8,169.4,169.0,167.6,167.2,167.0,142.6,136.6,135.0,133.7,133.5,132.8,132.1,130.2,129.2,128.8,128.7,128.6,128.5,128.4,127.2,126.5,84.5,81.0,79.1,76.5,75.6,75.1,74.4,72.1,68.2,68.0,66.8,58.5,52.6,45.5,43.2,35.5,26.8,22.7,22.2,20.9,14.8,9.6;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
58h
61nO
18, 1060; Measured value: 1060.
Embodiment 62: compound 62 synthetic
In 25mL round-bottomed flask, add successively 200mg (0.19mmol) compound 61,65mg (0.95mmol) imidazoles and 3mL solvent dimethylformamide, then add 143mg (0.95mmol) chlorotriethyl silane.At room temperature, stir 12 hours.React complete, reaction mixture distributes at saturated nacl aqueous solution (25mL) and ethyl acetate (25mL), isolates ethyl acetate layer.Ethyl acetate layer is further washed twice (25mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～60%) obtain 215mg compound 62.Productive rate: 96%.
Caryoplasm spectrum analysis:
1h NMR (500MHz, CDCl
3): δ 8.05 (d, J=7.8Hz, 2H), 7.66 (d, J=7.8Hz, 2H), 7.51 (t, J=7.8Hz, 2H), 7.42 (m, 3H), 7.21 – 7.23 (m, 12H), 6.97 (d, J=9.0Hz, 1H), 6.36 (s, 1H), 6.16 (t, J=7.8Hz, 1H), 5.95 (d, J=7.8Hz, 1H), 5.61 (d, J=7.2Hz, 1H), 5.52 (d, J=3.0Hz, 1H), 5.02 (dd, J=10.2, 7.8Hz, 2H), 4.86 (d, J=7.8Hz, 1H), 4.38 (m, 1H), 4.22 (m, 3H), 4.13 (m, 1H), 4.09 (s, 2H), 3.74 (d, J=6.0Hz, 1H), 2.43 (m, 1H), 2.37 (s, 3H), 2.31 (dd, J=15.0, 9.0Hz, 1H), 2.11 (dd, J=15.0, 9.0Hz, 1H), 2.07 (s, 3H), 1.97 (s, 3H), 1.81 (m, 1H), 1.60 (s, 3H), 1.15 (s, 3H), 1.07 (s, 3H), 0.83 (m, 9H), 0.48 (m, 6H),
13C?NMR(125MHz,CDCl
3):δ201.9,169.8,169.5,169.1,169.0,167.7,167.2,167.1,140.3,136.74,135.0,133.7,133.5,132.1,130.2,129.3,129.1,128.7,128.6,128.5,128.4,127.2,126.5,84.3,81.1,78.8,76.6,75.0,74.9,74.3,72.2,72.1,68.3,68.0,66.8,58.46,52.6,46.7,37.2,35.3,26.2,22.8,21.3,20.9,14.2,10.1,6.8,5.3;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
64h
75nO
18si, 1174; Measured value: 1174.
Embodiment 63: compound 63 synthetic
In 50mL round-bottomed flask, 200mg (0.17mmol) compound 62 is dissolved in 10.0mL methyl alcohol, and adds palladium-carbon of 20mg, at room temperature pass into hydrogen 2 hours.React complete, filter, be spin-dried for, silica gel column chromatography (eluent: chloroform: methyl alcohol/1～10%) obtain 150mg compound 63.Productive rate: 81%.
Caryoplasm spectrum analysis:
1h NMR (500MHz, DMSO-d
6): δ 7.87 (d, J=7.8Hz, 2H), 7.73 (d, J=7.8Hz, 2H), 7.62 (t, J=7.8Hz, 2H), 7.55 (m, 2H), 7.21 – 7.38 (m, 8H), 7.07 (s, 1H), 6.36 (s, 1H), 6.15 (s, 1H), 5.72 (t, J=7.8Hz, 1H), 5.41 (d, J=6.0Hz, 1H), 5.31 (m, 2H), 5.02 (dd, J=10.2, 7.8Hz, 2H), 4.82 (d, J=7.8Hz, 1H), 4.24 (m, 3H), 3.91 (m, 2H), 3.81 (m, 2H), 2.39 (s, 3H), 2.35 (m, 1H), 2.10 (s, 3H), 1.98 (s, 3H), 1.79 (s, 3H), 1.68 (s, 3H), 1.66 (m, 1H), 1.53 (m, 1H), 1.40 (s, 3H), 0.92 (s, 3H), 0.89 (s, 3H), 0.76 (m, 9H), 0.39 (m, 6H),
13C?NMR(125MHz,DMSO-d
6):δ201.7,171.7,170.3,170.2,169.5,169.3,166.9,166.8,165.7,139.8,137.8,137.7,134.6,134.0,131.9,130.3,130.0,129.2,128.8,128.7,128.0,127.9,83.6,80.3,77.0,75.7,75.0,74.8,74.7,72.3,71.4,67.1,58.0,54.5,46.2,43.3,37.1,34.7,26.8,22.9,21.8,21.5,21.0,14.1,10.3,7.0,5.1;
Caryoplasm spectrum analysis: ESI-MS, m/z[M+H]
+calculated value: C
57h
69nO
18si, 1084; Measured value: 1084.
Embodiment 64: covalent polymer 64 synthetic
In 5mL round-bottomed flask, add 100mg (0.64mmol) N, N'-carbonyl dimidazoles, in 56mg compound 63 and 3.0mL anhydrous dimethyl sulphoxide, continues to stir 2 hours.Then add 300mg hydroxyethylamyle (molecular-weight average is～6,000), in 3.0mL dimethyl sulfoxide (DMSO) and 200uL triethylamine, stirring at room 12 hours.Then add tetrabutyl ammonium fluoride, at room temperature stir 2 hours.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 251mg covalent polymer 64.This product absorbs at 280nm ultraviolet wavelength by contrast taxol, measures content of taxol 8% (w/w)
Synthetic route 14
Reaction conditions and reagent:
A) compound 21/2-[2-oxygen-(4-alkynes pentyloxy) oxyethyl group] acetic acid/N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (EDC)/DMAP (DMAP), chloroform, room temperature, 12h;
B) tetrakis triphenylphosphine palladium/1,3-dimethyl barbituric acid, chloroform, room temperature, 2h;
C) 6-nitrine-n-caproic acid/copper sulfate/gallic acid, dimethyl sulfoxide (DMSO), room temperature, 24h;
D) 12-amino-ethyl-bis-PEG ethyl nitrine [NH
2(PEG)
2n
3]/N, N'-carbonyl dimidazoles/triethylamine, dimethyl sulfoxide (DMSO), room temperature, 12h;
E) compound 66/ copper sulfate/gallic acid, dimethyl sulfoxide (DMSO), room temperature, 12h
Embodiment 65: compound 65 synthetic
In 50mL round-bottomed flask, add successively 277mg (1.39mmol) 2-[2-oxygen-(4-alkynes pentyloxy) oxyethyl group] acetic acid, 265mg (1.39mmol) N-(3-dimethylamino-propyl)-N-ethyl-carbodiimide hydrochloride (EDC) and 10mL anhydrous chloroform, at room temperature, stir 30 minutes.Then add 652mg (0.695mmol) compound 21 and 168mg (1.39mmol) DMAP (DMAP), continue to stir 12 hours.React complete, chloroform layer is washed twice (10mL * 2) and anhydrous magnesium sulfate drying with saturated nacl aqueous solution, filters, and is spin-dried for silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～50%) obtain 646mg compound 65.Productive rate: 83%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.03 (d, 2H, J=7.2Hz), 7.66 (d, 2H, J=7.2Hz), 7.52 (t, 2H, J=7.2Hz), 7.41 (m, 3H), 7.25 – 7.33 (m, 7H), 7.03 (d, 1H, J=7.8Hz), 6.29 (s, 1H), 6.15 (t, 1H, J=9.0Hz), 5.95 (dd, 1H, J=6.0, 3.5Hz), 5.87 (m, 1H), 5.60 (d, 1H, J=7.2Hz), 5.53 (d, 1H, J=2.8Hz), 5.42 (m, 1H), 5.23 (d, 1H, J=12.0Hz), 5.14 (d, 1H, J=12.0Hz), 4.88 (d, 1H, J=9.0Hz), 4.61 (m, 1H), 4.54 (m, 1H), 4.15-4.25 (m, 3H), 4.08 (m, 2H), 4.05 (d, 2H, J=7.2Hz), 3.87 (d, 1H, J=6.0Hz), 2.55 (m, 2H), 2.39 (s, 3H), 2.32 (m, 1H), 2.15 (m, 2H), 2.05 (s, 3H), 1.96 (s, 1H), 1.95 (s, 3H), 1.88 (m, 2H), 1.76 (m, 2H), 1.75 (s, 3H), 1.14 (s, 3H), 1.07 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.8,172.6,170.2,168.5,168.1,167.2,166.9,153.9,141.3,136.7,133.8,133.7,133.0,132.1,131.9,130.2,129.1,128.8,128.5,128.0,127.1,126.6,118.8,84.0,83.3,80.8,79.2,76.4,75.4,75.3,74.5,73.4,71.8,69.5,69.1,56.1,53.5,47.0,43.3,35.4,33.4,32.3,26.5,23.4,22.7,21.4,20.8,17.5,14.6,10.8;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
60h
66nO
22, 1121; Measured value: 1121.
Embodiment 66: compound 66 synthetic
In 25mL round-bottomed flask, add successively 320mg (0.309mmol) compound 65,29mg (0.024mmol) tetrakis triphenylphosphine palladium, 55mg (0.339mmol) 1,3-dimethyl barbituric acid, 5.0mL anhydrous chloroform, then at room temperature stirs 2 hours.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: ethyl acetate: sherwood oil/10～70%) purifying obtains 249mg compound 66.Productive rate: 75%.
Nmr analysis:
1h NMR (300MHz, CDCl
3): δ 8.05 (d, 2H, J=7.2Hz), 7.66 (d, 2H, J=7.2Hz), 7.51 (t, 2H, J=7.2Hz), 7.43 (m, 3H), 7.16 – 7.32 (m, 7H), 6.99 (d, 1H, J=9.0Hz), 6.20 (s, 1H), 6.17 (t, 1H, J=9.0Hz), 5.96 (d, 1H, J=7.2Hz), 5.69 (d, 1H, J=6.6Hz), 5.51 (s, 1H), 4.87 (d, 1H, J=9.0Hz), 4.43 (m, 1H), 4.21 (m, 1H), 4.11 (m, 3H), 4.08 (s, 2H), 3.72 (d, 1H, J=7.2Hz), 2.45 (m, 1H), 2.38 (s, 3H), 2.33 (m, 1H), 2.20 (m, 2H), 2.18 (s, 3H), 2.05 (m, 1H), 1.89 (s, 1H), 1.85 (m, 3H), 1.81 (t, 1H, J=12.1Hz), 1.72 (s, 2H), 1.59 (s, 3H), 1.14 (s, 3H), 1.04 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ201.7,170.5,169.7,169.6,168.9,168.8,167.8,167.3,166.9,153.9,141.1,136.7,133.7,133.6,132.8,132.0,131.9,130.2,129.2,129.1,129.0,128.5,127.2,126.5,118.7,83.9,82.7,78.8,76.4,75.4,75.3,74.6,74.3,72.1,69.4,69.3,68.2,68.0,63.4,56.1,52.8,47.0,43.3,35.4,33.6,27.3,26.5,22.6,21.4,20.7,15.1,14.5,10.7;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
56h
62nO
18, 1037; Measured value: 1037
Embodiment 67: compound 67 synthetic
In 10mL round-bottomed flask, add successively 73mg (0.07mmol) compound 66,50mg (0.32mmol) 6-azido--n-caproic acid, 2.0mL methyl alcohol, copper-bath (30uL * 1.0M) and gallic acid solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture, is spin-dried for, through silica gel column chromatography (eluent: chloroform: methyl alcohol/0～10%) purifying obtains 68mg compound 67.Productive rate: 82%.
Nmr analysis:
1h NMR (300MHz, CD
3oD): δ 8.07 (d, 2H, J=7.2Hz), 7.73 (s, 1H), 7.71 (d, 2H, J=7.2Hz), 7.56 (t, 2H, J=7.2Hz), 7.48 (t, 2H, J=7.2Hz), 7.39 (m, 3H), 7.34 (m, 4H), 7.16 (t, 1H, J=7.2Hz), 6.35 (s, 1H), 6.00 (t, 1H, J=6.0Hz), 5.81 (d, 1H, J=6.3Hz), 5.54 (d, 1H, J=6.3Hz), 5.50 (d, 1H, J=6.3Hz), 4.90 (d, 1H, J=9.0Hz), 4.23 (m, 4H), 4.11 (s, 2H), 4.04 (d, 2H, J=7.2Hz), 3.73 (d, 1H, J=7.2Hz), 3.21 (s, 2H), 2.62 (m, 2H), 2.42 (m, 2H), 2.30 (s, 3H), 2.22 (m, 2H), 2.05 (s, 3H), 1.95 (m, 3H), 1.83 (s, 3H), 1.81 (m, 2H), 1.71(t, 1H, J=12.1Hz), 1.55 (s, 3H), 1.51 (m, 2H), 1.22 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H),
13C?NMR(125MHz,CDCl
3):δ203.8,175.9,170.2,170.0,169.9,169.6,169.1,168.6,166.3,164.8,140.8,136.8,134.1,133.7,133.2,131.5,130.0,129.8,128.7,128.4,128.2,127.2,127.1,122.6,84.5,80.9,77.7,76.1,75.4,75.0,74.7,71.9,71.0,67.6,67.4,63.7,57.9,53.7,50.0,46.5,43.2,36.1,35.1,33.2,29.4,27.8,25.6,25.5,23.9,21.9,21.2,21.0,19.4,13.6,9.1;
Mass spectroscopy: ESI-MS, m/z[M+H]
+calculated value: C
62h
73n
4o
20, 1194; Measured value: 1194.
Embodiment 68: compound 68 synthetic
By 10.0g ganoderan, through activated carbon decolorizing, then through dextrane gel column chromatography, receipt molecular weight is 30,000-40,000 flow point, and lyophilize and 50 ℃ of vacuum-dryings obtain 651mg pale yellow powder.Getting molecular weight is 30,000-40,000 dry ganoderan and 100mg (0.64mmol) N of 300mg, and N'-carbonyl dimidazoles, puts into 5mL round-bottomed flask, adds 5mL dmso solution, is heated to 50 ℃ and stir 30 minutes.Then, add 30mg12-amino-ethyl-bis-PEG ethyl nitrine [NH
2(PEG)
2n
3] and 200uL triethylamine, stirring is spent the night.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 2.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 221mg covalent polymer 68.Productive rate: 73%.
Embodiment 69: covalent polymer 69 synthetic
In 10mL round-bottomed flask, add successively 170mg covalent polymer 68 (0.07mmol), 27mg (0.32mmol) compound 66, is dissolved in 3.0mL dimethyl sulfoxide (DMSO).Then, add copper-bath (30uL * 1.0M) and gallic acid solution (30uL * 1.0M), then at room temperature stir 2 days.React complete, reaction mixture methanol extraction, filters, and uses methanol wash 3 times.Then throw out is dissolved in 3.0mL distilled water, puts into dialysis tubing and dialyses.Dialyse complete, through lyophilize, obtain 126mg covalent polymer 69.This product absorbs at 280nm ultraviolet wavelength by control compound 67, measures content of taxol 5% (w/w).
Drug release test
In order to confirm that can saccharan Taxan covalent polymer discharge active bearing taxanes or derivatives thereof, we adopt rat plasma to shear the material that saccharan Taxan covalent polymer and HPLC/MS identify its release.
First measure pure taxol or docetaxel, pure taxol or the derivative of docetaxel, and their corresponding pure saccharan covalent polymers are at retention time (RT) and the molecular weight of HPLC/MS.Then, by material and the rat plasma temperature that will detect are incubated, resulting enzymatic product detects with HPLC/MS, contrasts with known substance.
Generally, we observe the pure Taxan of rat plasma catalysis (1) simultaneously, three reactions of the corresponding Taxane derivative that (2) are pure and (3) its polysaccharide covalent polymer.Drug release test program is as follows: get the material (100uM dimethyl sulfoxide solution) that 200uL measures, 200uL rat plasma, and 600uL phosphate buffered saline buffer (PH=7.4), be configured to 1.0mL reaction mixture.Then, get immediately 100uL reaction mixture, with 90% acetonitrile precipitation protein the centrifugal supernatant liquor that separates, as the detection reaction product of 0 minute.Remaining 900uL reaction mixture is incubated 30 minutes 37 ℃ of temperature, then gets 100uL reaction mixture, with 90% acetonitrile precipitation protein the centrifugal supernatant liquor that separates, as the detection reaction product of 30 minutes.These supernatant liquors, after filtration, analyze through HPLC/MS.Compound 67 and covalent polymer 69 drug release experiment (see figure 2)s
Based on above-mentioned experimental result, contriver finds: the compounds of this invention 67 and Taxan covalent polymer 69, in animal plasma, quick-release discharges the former medicine of Taxan soon.
Antitumor cytolytic activity
In order to measure the activity of intermediate and the synthetic saccharan yew alkanes covalent polymer of synthesized, we are with adopting conventional mtt assay to evaluate their anti-tumor activity.
Mtt assay is a kind of method that detects cell survival and growth. its detection principle is that the succinodehydrogenase in viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and dead cell is without this function. the first a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, with enzyme-linked immunosorbent assay instrument, at 490nm wavelength place, measure its absorbance value, can indirectly reflect viable cell quantity. within the scope of certain cell count, the amount that MTT crystallization forms is directly proportional to cell count. and the activity that the method has been widely used in some biologically active factorss detects, large-scale screening anti-tumor medicine, cell toxicity test and tumor radiosensitivity mensuration etc.
MCF-7 tumour cell or PC3 tumour cell suspension inoculation, in 96 porocyte culture plates, are cultivated to certain hour in 37 ℃, 5%CO2 incubator.From incubator, take out 96 well culture plates, add respectively different compounds or saccharan medicine covalent polymer, every kind of compound or saccharan medicine covalent polymer are established seven concentration and are respectively 400nM, 200nM, 100nM, 50nM, 25nM, 12.5nM, 6nM, 3nM and 1nM.Each concentration is established three multiple holes and is established blank (containing tumour cell, replacing compound or saccharan medicine covalent polymer with nutrient solution) simultaneously, cultivates 72 hours.Then abandon supernatant liquor, every hole adds 20uL3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt (MTT), cultivate 4 hours for 37 ℃, abandon the every hole of supernatant liquor and add 100uL DMSO solution, after vibration 5min, by microplate reader, measure the light absorption value (A value) at 490nm place, calculate the half-inhibition concentration (IC of each compound or saccharan medicine covalent polymer
50value).The growth inhibition ratio of each drug level group (%)=(the average OD value of the average OD value/control wells of 1-experimental port) * 100%; IC
50value=lg
-1[Xm-i (Σ P-0.5)], repeats 3 times, averages.Xm: the logarithmic value of the peak concentration of design; I: the logarithmic value of each concentration multiple proportions concentration; Σ P: each organizes growth inhibition ratio sum; 0.5: empirical constant.
The IC of table 2. taxanes compounds and saccharan taxanes covalency body polymkeric substance inhibition tumor cell
50value
NT is not test; * be equivalent nM concentration.
Based on above-mentioned experimental result, contriver finds:
(1) covalent polymer of the present invention has the MCF-7 of killing tumour cell or PC3 activity of tumor cells;
(2) taxol or docetaxel, after connecting degradable structural unit of the present invention, still retain anti-tumor activity;
(3) also find, when water-soluble saccharan or degradable structural unit are connected to the 2'-hydroxy position of taxol or Docetaxel, keep excellent anti-tumor activity.
Claims (12)
1. the water-soluble saccharan Taxan of general formula (I) covalent polymer, or its pharmacy acceptable salt or solvate,
Wherein water-soluble saccharan is selected from homopolysaccharide or mixed polysaccharide, (as the cyclodextrin) that it is that be straight chain, side chain or annular; Described bearing taxanes is selected from take compound and the derivative thereof that Taxan diterpene is parent nucleus, as taxol (Taxol), Docetaxel (docetaxel, docetere).
Described degradable structural unit can be straight chain, side chain or annular, is selected from and contains ester bond, amido linkage, isourea key, amino-formate bond, amino bamic acid ester bond, thiocarbamide key, disulfide linkage, carbonic acid ester bond, phosphoric acid ester bond; Or containing triazole and the derivative condensed ring fragment of triazole [as 1,6a-pyrrolin [3,4-d] triazole-4 also, 6(5aH, 5H)-diketone], 2-alkyl sulphur succinic acid lactan; Or containing the structure fragment of aryl, heteroaryl or fatty group etc.
Preferably, described water-soluble saccharan is selected from the polysaccharide of vegetable polysaccharides, animal polysaccharide, microbial polysaccharide or synthetic.
More preferably, the sugar unit of described homopolysaccharide is selected from five-carbon sugar, hexose, seven carbon sugar, eight carbon sugar etc., for example dextran, xylan.The sugar unit of described mixed polysaccharide is mixed and is formed by above-mentioned homopolysaccharide unit, preferably transparent matter acid etc.
Also more preferably, the glycosidic bond between the sugar unit of described homopolysaccharide or mixed polysaccharide can be α type (as water soluble starch), or β type (as water soluble cellulose), or α, β mixed type.
Further preferably, the sugar unit of described water-soluble saccharan, is selected from the substituent sugar unit of Rb (as hydroxyethylamyle), natural desoxy sugar unit (as rhamnosyl), aminosugar unit (as galn, sialic acid, chitosan) etc.Wherein Rb is selected from ethanoyl (as chitin), carboxylic acid group, carboxylic acid sodium base, sulfonic group, sodium sulfonate group, hydroxyethyl, methyl, acyl group or hydroxypropyl etc.
Still more preferably, described water-soluble saccharan is hyaluronic acid, xylan, water soluble starch, hydroxyethylamyle, water soluble cellulose, galn, sialic acid, rhamnosyl, left-handed glucosides, dextran.Most preferably be dextran, hyaluronic acid, hydroxyethylamyle, ganoderan.
2. Taxan covalent polymer according to claim 1, is characterized in that, the general formula of described degradable structural unit is as shown in the table:
Table 1. degradable structural unit general formula
In said structure general formula, optional water-soluble saccharan or the Taxan of connecting of left end or right-hand member
Y
1be selected from O, S, NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl); Y
2be selected from O, NH or S; Y
3be selected from O or NR (R is H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl); The integer of n=0-10;
Z
1, Z
2, Z
3, Z
4, Z
5, Z
6be selected from straight-chain alkyl, branched hydrocarbyl, containing heteroatomic straight-chain alkyl, containing heteroatomic branched hydrocarbyl, unsaturated straight-chain alkyl, unsaturated side chain alkyl, containing heteroatomic unsaturated straight-chain alkyl, containing heteroatomic unsaturated side chain alkyl, saturated cyclic, unsaturated cyclic hydrocarbon radical, containing heteroatomic cyclic hydrocarbon radical, containing heteroatomic unsaturated cyclic hydrocarbon radical, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl etc.Described Z
1, Z
2, Z
3, Z
4, Z
5, Z
6optionally by Ra, replaced;
X
1, X
2, X
3, X
4, X
5, X
6be selected from independently of one another amino acid and (comprise D and L-type amino acid, the amino acid of natural amino acid and synthetic; Also comprise α, beta, gamma, δ, and epsilon-amino acid; β-alanine for example, γ-aminobutyric acid or epsilon-amino caproic acid) or amino acid whose N-hydrocarbylation derivative;
L
1, L
2, L
3be selected from independently of one another O, NH, S, straight-chain alkyl, branched hydrocarbyl, containing heteroatomic straight-chain alkyl, containing heteroatomic branched hydrocarbyl, unsaturated straight-chain alkyl, containing heteroatomic unsaturated straight-chain alkyl, saturated cyclic, unsaturated cyclic hydrocarbon radical, containing heteroatomic saturated cyclic, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, shorter polymer segments (polyoxyethylene glycol that is 100～20000 such as molecular weight (PEG), polymeric amide, PLGA (PLGA)) etc.L
1, L
2, L
3optionally by Ra, replaced;
Ra is selected from hydrogen, halogen, C
1-6alkoxyl group, C
1-6alkyl, cyano group, amino, nitro, C
1-6alkylamino or two (C
1-6alkyl) amino.
3. be selected from the covalent polymer of following structure:
4. a functionalization Taxane derivative that contains degradable group for general formula (II), is characterized in that
Wherein R4 is selected from benzoyl or tertiary fourth oxygen acyl group (BOC);
R1, R2 and R3 are selected from independently of one another:
(1) H, ethanoyl, allyloxycarbonyl, benzyl oxygen carbonyl, tertiary butyl dimethylsilyl, triethyl silyl, TMS;
(2) be selected from following formula III-1, III-2, III-3, III-4, the substituting group containing 1,2,3-triazole of III-5 or III-6;
Formula III-1, III-2, III-3, III-4, in III-5 or III-6, n is identical or different separately, is selected from the integer of 0-20.
X
1, X
2be selected from independently of one another O, S, NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl) or straight-chain alkyl, for example (CH
2)
1-20; Or for example, containing heteroatomic straight-chain alkyl, [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20;
Ar is that aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, shorter polymer segments are as [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20;
（3）
Wherein, the covalent linkage that connects Taxan described in is selected from ester bond, amino-formate bond, carbonic acid ester bond, thiocarbamate key, phosphoric acid ester bond, isourea key;
Described spacer is straight chain, side chain or annular, is for example selected from, containing heteroatomic straight-chain alkyl, [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20, 1-20 amino acid whose peptide fragment; Shorter polymer segments, for example molecular weight is 100～20,000 polyoxyethylene glycol (PEG), polymeric amide, PLGA (PLGA); Or the fragment of amide bond, ester bond, substituted-amino; Or containing the structure fragment of aryl, heteroaryl or fatty group.
X is functional group, is selected from azido-(N
3), the amino SR ' of alkynyl (C ≡ CH), amino, the amino HNR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl) replacing, sulfydryl, replacement (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl), carboxyl, fat base, amide group or protection amino and contain the fragment of toxilic acid lactan;
(4) as shown in the formula containing azido-(N shown in IV
3) or the amino SR ' of the amino substituting group of the amino HNR ' of acetylene bond, amino, replacement (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl), carboxyl, fat base, amide group or protection, sulfydryl, replacement and containing the fragment of toxilic acid lactan:
In formula, n is identical or different separately, is selected from the integer of 0-20;
X
1, X
2, X
3be selected from independently of one another O, NH, S, NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl) or straight-chain alkyl, for example (CH
2)
1-20; Or containing heteroatomic straight-chain alkyl; [CH for example
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20; In addition, X
1also be selected from dibasic cyclic hydrocarbon radical, dibasic containing heteroatomic ring alkyl, dibasic aromatic base or dibasic containing heteroatoms aromatic base;
X
a, X
b, X
c, X
d, X
e, X
f, X
g, X
h, X
i, X
jbe selected from independently of one another any one natural or non-natural amino acid;
Y
1, Y
2be selected from independently of one another O, S or NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl);
R is selected from independently of one another into H, allyl group, benzyl,, allyloxycarbonyl silica-based to methoxybenzyl, trialkyl, benzyl oxygen carbonyl and containing the fragment of toxilic acid lactan etc.;
T is selected from azido-(N independently of one another
3), the amino of amino, protection, sulfydryl, the sulfydryl of protection, the amino of replacement or alkynyl and containing the fragment of toxilic acid lactan;
Ar is selected from aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, shorter polymer segments as [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20;
(5) or containing aromatic base phosphine, or containing the substituting group of aromatic base phosphine boron trihydride mixture.
5. functionalization Taxane derivative according to claim 4, is characterized in that, described derivative is selected from following structure:
6. the water-soluble saccharan with functionalization group of a class functionalization, its structure is composed as follows to be stated shown in general formula V:
Wherein water-soluble saccharan is selected from homopolysaccharide or mixed polysaccharide, and it is (as cyclodextrin) straight chain, side chain or annular;
Described spacer be straight chain, side chain, annular, for example, containing heteroatomic straight-chain alkyl, [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20deng; Can also be that 1-20 amino acid forms little peptide fragment, or shorter polymer segments, if molecular weight is 100～20,000 polyoxyethylene glycol (PEG), polymeric amide, PLGA (PLGA) etc.; Or the fragment of amide bond, ester bond, substituted-amino; Or containing the structure fragment of aryl, heteroaryl or fatty group.
Described functional group is selected from functional group and is selected from azido-(N
3), alkynyl (C ≡ CH), thiazolinyl (CH=CH
2), the amino HNR ' of sulfydryl, carboxyl, ester group, sulfonic group, amide group, amino, replacement (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl) or protection amino and containing the fragment of toxilic acid lactan.
The covalent linkage of described connection polysaccharide, the triazole that is selected from ester bond, amido linkage, isourea key, amino-formate bond, amino bamic acid ester bond, thiocarbamide key, disulfide linkage, carbonic acid ester bond, phosphoric acid ester bond or formation covalent linkage, 2-alkyl sulphur succinic acid lactan etc.;
The water-soluble polysaccharide of described functionalization preferably has following structure:
In formula, n is identical or different separately, is selected from 0-20, preferably 1-10, the more preferably integer of 2-6;
X
1, X
2be selected from independently of one another O, S, NR ' (R ' be the substituting group of H or an any type), straight-chain alkyl ((CH for example
2)
1-20; Or for example, containing heteroatomic straight-chain alkyl ([CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20, [CH
2cH
2sCH
2cH
2]
1-20) or with the substituent alkyl of Ra; Ra is selected from hydrogen, halogen, C
1-6alkoxyl group, C
1-6alkyl, cyano group, amino, nitro, C
1-6alkylamino or two (C
1-6alkyl) amino;
Y
1, Y
2, Y
3be selected from independently of one another O, S or NR ' (R ' be H, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl);
X
a, X
b, X
c, X
d, X
e, X
f, X
g, X
h, X
i, X
jcan be selected from independently of one another any one natural or non-natural amino acid;
Q substituting group is selected from H, carboxyl, azido-(N independently of one another
3), the amino of the amino or protection of alkynyl, amino, replacement, sulfydryl, isothiocyano, different oxygen cyano group and containing the fragment of toxilic acid lactan.；
Ar is selected from aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, shorter polymer segments as [CH
2oCH
2]
1-20, [CH
2sCH
2]
1-20, [CH
2cH
2oCH
2cH
2]
1-20,, [CH
2cH
2sCH
2cH
2]
1-20.
7. the water-soluble polysaccharide of functionalization according to claim 6, is characterized in that, the water-soluble polysaccharide of described functionalization is selected from following structure:
8. a preparation method for the covalent polymer of claim 1-5 any one, is characterized in that, described method comprises the steps:
(1) with hydroxyl protection reagent, protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently, with 7 of hydroxyl protection reagent protection taxanes chemical combination or/and 10 alcoholic extract hydroxyl groups;
(3) optionally, slough the hydroxyl protection reagent in step (1); Spacer with functional group is connected on 2 ' position of bearing taxanes;
(4) optionally, de-7 or/and the protecting group on 10 alcoholic extract hydroxyl groups, obtain the Taxane derivative of functionalization;
(5) optionally, water miscible saccharan is connected with the spacer with functional group, obtains the water miscible saccharan (wherein water-soluble saccharan carry out the object of functionalization be in order to connect fat-soluble bearing taxanes) of functionalization;
(6) under the effect of catalyzer or coupling agent, the Taxane derivative of step (4) functionalization is reacted with the water-soluble saccharan that water-soluble saccharan or step (5) obtain functionalization, obtain covalent polymer of the present invention.
9. a preparation method for the covalent polymer of claim 1-5 any one, is characterized in that, described method comprises the steps:
(1) with hydroxyl protection reagent, protect 2 of bearing taxanes ' position alcoholic extract hydroxyl group;
(2) subsequently, will with the spacer of functional group, receive 7 of bearing taxanes or/and on 10 alcoholic extract hydroxyl groups;
(3) selectivity is sloughed the hydroxyl protection reagent in step (1), obtains the Taxane derivative of functionalization,
(4) optionally, water miscible saccharan is connected with the spacer with functional group, obtain functionalization water miscible saccharan (wherein water-soluble saccharan carry out the object of functionalization be in order to connect fat-soluble bearing taxanes);
(5), under the effect of catalyzer or coupling agent, the Taxane derivative of the functionalization that step (3) is obtained reacts with the water-soluble saccharan of the functionalization that water-soluble saccharan or step (4) obtain, and obtains covalent polymer of the present invention.
10. a pharmaceutical composition, its formula that comprises claim 1-6 any one (I) covalent polymer, formula (II) or formula (III) compound or its pharmacy acceptable salt, and pharmaceutically acceptable conventional medicine vehicle or assistant agent.Preferably, described pharmaceutical composition contains the compounds of this invention or the covalent polymer of 0.1-95% weight conventionally.
11. 1 kinds of pharmaceutical preparations, its behaviour with medicament or animal medicament, it is characterized in that, the formula that described preparation comprises claim 1-6 any one (I) covalent polymer, formula (II) or formula (III) compound or its pharmacy acceptable salt, and pharmaceutically acceptable conventional medicine vehicle or assistant agent.Preferably, pharmaceutical preparation can be liquid dosage form or solid dosage.Described liquid dosage form can be true solution, colloidal type, particulate formulations, mixed suspension form; Described solid dosage can be tablet, capsule, dripping pill, aerosol, pill, pulvis emulsion, granule, suppository, freeze-dried powder etc.More preferably, described pharmaceutical preparation can ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation or various particulate delivery system.
Formula (I) covalent polymer of 12. claim 1-6 any one, formula (II) or formula (III) compound, and the application of pharmacy acceptable salt in preparing antitumor drug.Preferably, described tumour is selected from: mammary cancer, lung cancer, oral carcinoma, liver cancer, intestinal cancer, cancer of the stomach, blood cancer, bladder cancer, carcinoma of the pancreas, uterus carcinoma, skin carcinoma.More preferably, the dosage of described compound is 0.5～500 mg/kg of the therapeutic dose that is equivalent to taxol or docetaxel.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923217A (en) * | 2014-04-17 | 2014-07-16 | 陕西师范大学 | 6-amino caproic acid cellulose ester as well as synthetic method and application thereof |
| CN106421808A (en) * | 2016-09-19 | 2017-02-22 | 华中科技大学 | Preparation and application of hydroxyethyl starch modified anti-tumor medicine conjugate and assembling nanometer system thereof |
| WO2017049821A1 (en) * | 2015-09-26 | 2017-03-30 | 南京友怡医药科技有限公司 | Water-soluble docetaxel anticancer drug compound and preparation method and use thereof |
| CN108219029A (en) * | 2018-03-22 | 2018-06-29 | 盐城师范学院 | A kind of preparation method of water solubility Cabazitaxel anticancer drug |
| CN108467439A (en) * | 2018-03-22 | 2018-08-31 | 盐城师范学院 | A kind of preparation method of water-soluble paclitaxel anticancer drug |
| CN108524947A (en) * | 2018-05-04 | 2018-09-14 | 北京林业大学 | A kind of ganoderma lucidum polysaccharide-phenyl boric acid-methotrexate (MTX) conjugate medicine-carried nano particles and preparation method thereof with pH responses |
| CN110201182A (en) * | 2019-06-21 | 2019-09-06 | 山东大学 | A kind of taxol-DHA- dextran coupling polymer and its synthetic method and application |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1440748A (en) * | 2003-03-14 | 2003-09-10 | 南开大学 | Water soluble anticancer medicine taxol composite and its prepn |
| CN1648132A (en) * | 2004-01-19 | 2005-08-03 | 中国人民解放军军事医学科学院毒物药物研究所 | Taxinol water soluble derivative |
| CN1705683A (en) * | 2002-10-18 | 2005-12-07 | 菲迪尔制药公司 | Taxanes covalently bounded to hyaluronic acid or hyaluronic acid derivatives |
| US20080153865A1 (en) * | 1998-03-30 | 2008-06-26 | Pg-Txl Company, L.P. | Water soluble paclitaxel derivatives |
| CN102266568A (en) * | 2011-08-01 | 2011-12-07 | 扬州大学 | Preparation method for hydroxypropyl cyclodextrin inclusion of taxol |
| CN102302786A (en) * | 2011-08-01 | 2012-01-04 | 扬州大学 | Preparation method for beta-cyclodextrin polymer-paclitaxel inclusion compound |
-
2013
- 2013-11-27 CN CN201310616253.7A patent/CN103641925B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080153865A1 (en) * | 1998-03-30 | 2008-06-26 | Pg-Txl Company, L.P. | Water soluble paclitaxel derivatives |
| CN1705683A (en) * | 2002-10-18 | 2005-12-07 | 菲迪尔制药公司 | Taxanes covalently bounded to hyaluronic acid or hyaluronic acid derivatives |
| CN1440748A (en) * | 2003-03-14 | 2003-09-10 | 南开大学 | Water soluble anticancer medicine taxol composite and its prepn |
| CN1648132A (en) * | 2004-01-19 | 2005-08-03 | 中国人民解放军军事医学科学院毒物药物研究所 | Taxinol water soluble derivative |
| CN102266568A (en) * | 2011-08-01 | 2011-12-07 | 扬州大学 | Preparation method for hydroxypropyl cyclodextrin inclusion of taxol |
| CN102302786A (en) * | 2011-08-01 | 2012-01-04 | 扬州大学 | Preparation method for beta-cyclodextrin polymer-paclitaxel inclusion compound |
Non-Patent Citations (3)
| Title |
|---|
| 杜文婷等: "紫杉醇水溶性衍生物的研究进展", 《中国现代应用药学杂质》, vol. 22, no. 1, 28 February 2005 (2005-02-28) * |
| 杨媛: "乳糖基化紫杉醇衍生物的制备及其靶向性考察", 《2006第六届中国药学会学术年会论文集》, 31 December 2006 (2006-12-31) * |
| 杨恩慈: "改善紫杉醇水溶性方法的研究进展", 《中国药学》, vol. 9, no. 8, 31 August 2011 (2011-08-31) * |
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| US10406239B2 (en) | 2015-09-26 | 2019-09-10 | Nanjing Youyi Medical Technology Co., Ltd | Water-soluble docetaxel anticancer drug compound and preparation method and use thereof |
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| CN112351976A (en) * | 2018-06-20 | 2021-02-09 | 圣多利康制药责任有限公司 | Taxane-lipid-polysaccharide double-type couplet, preparation method and application thereof |
| CN112351976B (en) * | 2018-06-20 | 2024-04-19 | 圣多利康制药责任有限公司 | Taxane-lipid-polysaccharide double-type coupling body, preparation method and application thereof |
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| CN110201182B (en) * | 2019-06-21 | 2022-09-27 | 山东大学 | paclitaxel-DHA-dextran coupling polymer and synthetic method and application thereof |
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