CN104650342A - Highly-branched polymerized prodrug, and applications thereof - Google Patents
Highly-branched polymerized prodrug, and applications thereof Download PDFInfo
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- CN104650342A CN104650342A CN201310581715.6A CN201310581715A CN104650342A CN 104650342 A CN104650342 A CN 104650342A CN 201310581715 A CN201310581715 A CN 201310581715A CN 104650342 A CN104650342 A CN 104650342A
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- 0 C*c(c(C)c1)cc2c1OCO2 Chemical compound C*c(c(C)c1)cc2c1OCO2 0.000 description 12
- KAPAJCPOBXIQRP-UHFFFAOYSA-N Nc(c(C=O)c1)cc2c1OCO2 Chemical compound Nc(c(C=O)c1)cc2c1OCO2 KAPAJCPOBXIQRP-UHFFFAOYSA-N 0.000 description 1
- HGPFZPZOCKMATQ-UHFFFAOYSA-N OC(C(C=C1N2Cc3cc(CC4OCOC4=C4)c4nc13)=C(CO1)C2=O)C1=O Chemical compound OC(C(C=C1N2Cc3cc(CC4OCOC4=C4)c4nc13)=C(CO1)C2=O)C1=O HGPFZPZOCKMATQ-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a highly-branched polymerized prodrug, and applications thereof, and more specifically relates to a highly-branched polymerized prodrug with a structure represented by formula (I), or a pharmaceutically acceptable salt of the highly-branched polymerized prodrug. The highly-branched polymerized prodrug and the pharmaceutically acceptable salt thereof possess excellent curative effects on topoisomerase I related diseases of experimental mammals in vivo, and especially on solid tumor of experimental mammals in vivo. When in vivo activity is equal to in vitro activity on cancer cell propagation inhibition, in vivo medical half-life period and detention time are more reasonable; clearance rate is reduced greatly; and it is more beneficial for determining administration method and reducing administration times; and development of a novel generation of antitumor drug is possible.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of new higly branched chain polymeric drug precursor or its pharmacy acceptable salt and application thereof.
Background technology
Camptothecine (Camptothecin, CPT) be a kind of cytotoxic alkaloid extracted from Nyssaceae plant camptotheca acuminata (Camptothecaacuminata) for 1966, there is obvious anti-tumor activity, especially stronger to digestive tract tumor, leukemia, bladder cancer isoreactivity, also found that camptothecin analogues all can rotate copying and transcribe DNA in equimolecular activity and lax necessary topoisomerase produces restraining effect afterwards.Camptothecine can be stablized and form a reversible enzyme-camptothecine-DNA ternary compound, namely this formation of dividing compound can prevent the reconstitution steps in topoisomerase schizokinesis/combined cycle process, and prior art has reported that topoisomerase I supressor is effective for treatment HIV.But limit its clinical application due to its poorly water-soluble, camptothecine and analogue thereof have following structure:
These derivative compounds with parent camptothecin structure all containing a five-ring group, this five-ring with lactonic ring E on have an asymmetric center, lactonic ring E contains the structure of a 20S-.This five-ring group also contains the hexa-atomic lactone (ring E) of 20-hydroxyl containing pyrrolo-[3, a 4-b] quinoline (ring A, B and C), the pyridinium acetate (ring D) of a conjugation and one.Wherein, A ring can be replaced by OH in 10-position and/or 11-position, can also be replaced by straight or branched alkyl or alkoxyl group, or is connected with ring by heteroatoms (i.e. O or S).Such as, 10-hydroxycamptothecine, 11-hydroxycamptothecine and 10,11-dihydroxyl camptothecin analogues are all natural products, and those skilled in the art adopt currently known methods just can convert thereof into the various camptothecin analogues containing substituted radical.B ring can in 7-position by straight or branched alkyl, substituted alkyl, cycloalkyl, alkoxyl group, benzyl, amino, the replacements such as aminoalkyl group, alkyl carbamate, alkyl carbohydrazide, phenylhydrazine derivatives.Other replacement may in C, D and E ring.Representative camptothecin analogues comprises camptothecine, topotecan (topotecan), Rinotecan (CPT-11), SN38 and FL118 etc.See US5004758; US4943579; USRE32518, its content is hereby incorporated by.Because these derivative major parts are all water insoluble, therefore, camptothecine is be applied to clinical experiment with the form of water-soluble carboxyl acid esters at first, and the lactonic ring of this carboxylicesters opens formation sodium salt.Although relative to camptothecine itself, this sodium salt has water-soluble preferably, and it has stronger toxicity, and cancer resistance in body is also very little, and therefore this method is worthless.
In order to improve the water-soluble poor defect of camptothecin analogues, keeping Cytotoxic while, those skilled in the art attempt manyly improving the water-soluble of camptothecin analogues by modifying A ring and/or B ring or 20-hydroxyl.Such as, topotecan (topotecan) (9-dimethylaminomethyl-10-hydroxyl CPT) and Rinotecan (irinotecan) (7-ethyl-10 [4-(1-piperidines)-1-piperidines] ketonic oxygen CPT) (also known as CPT-11) are exactly two water-soluble CPT derivatives, and they all possess effective clinical effectiveness.But, still there is a lot of technical barriers, such as medicine water-soluble poor, toxicity, bioavailability are low, unstable and the fast degradation etc. in body.Although once there was the method much attempting to improve administration, there is no a kind of method not Shortcomings part.Such as, for solving or being at least that the medication generally adopted improving these weak points one or more comprises drug pack, as in liposome, polymer matrix or unimolecular micelle, with water soluble polymers (as a polyethylene glycol) covalent bonds, utilize assignment of genes gene mapping agent, or the method similar to these.For many years, have many methods to be proposed to improve the administration of biologically active agent, usually cause efficiency very low because drug loading efficiencies is low with liposome encapsulation, cost benefit is not good.And the active agent release rates in liposome depends on the Dissolution and dissociation of liposome, to lipid layers be passed through during promoting agent diffusion in other words, which limits the practical efficiency of biosystem for promoting agent.In addition, the structure of liposome usually can only be used for fat-soluble medicine.Structure based on polymer matrix has similar deficiency usually, as good administration medicine system characteristic cannot be obtained, particularly those crosslinked polymers, those release rate that may discharge the promoting agent of water miscible degradable polymer matrix are unstable for another example.By contrast, a promoting agent and polymer such as the conjugation of polyethylene glycol can provide a clearer and more definite alternative approach, this is because this conjugation itself usually, although always not, good delivery properties can be provided, particularly in polymer and promoting agent connection on location.But the compound based on protein comprises the mixture containing isomers, the position that polymer chain is combined with specific protein and quantity usually change to some extent, and this is by the problem of repeatable for the appearance that causes when preparing these components aspect.
Therefore, in the urgent need to a kind of demand improving medication, this method is by reducing clean-up time, improving biological activity and efficiency, and reduction side effect reaches optimal bioavailable sexual balance.
Summary of the invention
In order to solve problems of the prior art, contriver is after have extensively studied the PEG technology (PEGylation) of camptothecine and analogue thereof, after finding the PEG through modifying, camptothecine and analogue thereof have higher activity, stability and bioavailability all improve a lot, when the external activity of anticancer propagation is suitable, there is more reasonably drug half-life, residence time in vivo, significantly reduce clearance rate, more be conducive to the administering mode determining medicine, reduce administration number of times, be expected to be developed to antitumor drug of new generation.
The higly branched chain polymeric drug precursor that one aspect of the present invention provides one to have formula (I) structure or its pharmacy acceptable salt,
Wherein, A is selected from following structure:
R
1, R
2, R
3, R
4be selected from hydroxyl, sulfydryl, C independently of one another
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-O-C (O) R
12,-NR
13r
14,-N (R
12)-C (O) OR
12or formula (B) substituting group,
Condition is R
1, R
2, R
3, R
4at least one is selected from formula (B) substituting group;
Wherein said C
1-8alkyl, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl or 5-10 unit heteroaryl are independently optionally selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C by one or more separately further
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced;
In the present invention, R
1, R
2, R
3, R
4four groups are all selected from the substituent compound of formula (B) structure and can be called for short four arm compounds; R
1, R
2, R
3, R
4wherein three groups are selected from formula (B) structure substituting group, and another substituting group is selected from the substituent compound of non-formula (B) structure can be called for short three arm compounds; R
1, R
2, R
3, R
4wherein two groups are selected from formula (B) structure substituting group, and another two substituting groups are selected from the substituent compound of non-formula (B) structure can be called for short two arm compounds; R
1, R
2, R
3, R
4one of them group is selected from formula (B) structure substituting group, and another three substituting groups are selected from the substituent compound of non-formula (B) structure can be called for short single armed compound.
R
5, R
6be selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14;
Wherein said C
1-8alkyl, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl or 5-10 unit heteroaryl are independently optionally selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C by one or more separately further
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced;
R
7, R
8, R
9be selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14;
Wherein said C
1-8alkyl, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl or 5-10 unit heteroaryl are independently optionally selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C by one or more separately further
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced;
R
10and R
11be fused into 5-7 unit cycloalkyl, 5-7 unit heterocyclic radical, 5-7 unit's aryl or 5-7 unit heteroaryl with the phenyl be connected, be selected from following structure with the structure that the phenyl be connected is formed jointly:
Wherein 5-7 unit cycloalkyl, 5-7 unit heterocyclic radical, 5-7 unit's aryl or 5-7 unit heteroaryl are optionally selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced;
R
12, R
13, R
14be selected from hydrogen, C
1-4alkyl;
L is difunctional connection base, is selected from native amino acid residues;
M is 0,1,2;
N is positive integer;
P, q, t are 0,1,2,3 or 4.
As further preferred scheme, difunctional connection base L can be selected from L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, glycine, Serine, Threonine, methionine(Met), halfcystine, phenylalanine, tryptophan residue and/or its combination; Preferred L-Ala or glycine residue; Most preferably glycine residue.
As further preferred scheme, when A is
form formula (II) compound
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
10, R
11, R
12, R
13, R
14, L, m, n, f definition as described in general formula (I).
As further preferred scheme, work as R
7, R
8when being hydrogen, form formula (II-a) compound:
R
1, R
2, R
3, R
4, R
5, R
6, R
10, R
11, R
12, R
13, R
14, L, m, n, r definition as described in general formula (I), condition is when m is 1, R
5, R
6be asynchronously hydrogen.
As further preferred scheme, work as R
5, R
6be hydrogen, m be when being 2, form formula (II-a-1) compound:
R
1, R
2, R
3, R
4, R
10, R
11, R
12, R
13, R
14, L, n, r definition as described in general formula (I).
As further preferred scheme, be selected from as shown in the formula (II-a-1-1) compound:
N definition is as described in general formula (I).
As further preferred scheme, when m is 1, R
5, R
6one of be selected from hydrogen, another is selected from methyl, forms formula (II-a-2) compound:
R
1, R
2, R
3, R
4, R
10, R
11, R
12, R
13, R
14, L, n, r definition as described in general formula (I).
As further preferred scheme, be selected from (II-a-2-1) compound:
N definition is as described in general formula (I).
As further preferred scheme, when A is
m is 1, R
5, R
6, R
7, R
8when being hydrogen, form formula (II-b) compound simultaneously:
R
1, R
2, R
3, R
4, R
10, R
11, R
12, R
13, R
14, L, n, r definition as described in general formula (I), n is here actual refers to n+1, and because n gets positive integer, n+1 numerical value equally also gets positive integer, therefore, is adjusted to n here by n+1, gets positive integer, and following m is 1, R
5for hydrogen, R
6during for hydrogen, n+1 is adjusted to n equally, gets positive integer.
As further preferred scheme, be selected from formula (II-b-1) compound:
N definition is as described in general formula (I).
As further preferred scheme, when A is
time, form formula (III) compound:
R
1, R
2, R
3, R
4, R
5, R
6, R
9, R
10, R
11, R
12, R
13, R
14, L, m, n, p, q, t, r definition as described in general formula (I).
As further preferred scheme, when m is 1, form formula (III-a) compound:
R
1, R
2, R
3, R
4, R
5, R
6, R
9, R
10, R
11, R
12, R
13, R
14, L, n, p, q, t, r definition as described in general formula (I).
As further preferred scheme, work as R
5, R
6when being hydrogen, form formula (III-a-1) compound:
R
1, R
2, R
3, R
4, R
9, R
10, R
11, R
12, R
13, R
14, L, n, p, q, t, r definition as described in general formula (I).
As further preferred scheme, be selected from formula (III-a-1-1) compound:
Or be selected from formula (III-a-1-2) compound:
Or formula (III-a-1-3) compound:
N definition is as described in general formula (I).
As further preferred scheme, when m is 0 or 2, R
5, R
6when being hydrogen, form formula (III-b) compound:
R
1, R
2, R
3, R
4, R
9, R
10, R
11, R
12, R
13, R
14, L, n, p, q, t, r definition as described in general formula (I).
As further preferred scheme, when p is 0, form formula (III-c) compound:
R
1, R
2, R
3, R
4, R
5, R
6, R
10, R
11, R
12, R
13, R
14, L, m, n, q, t, r definition as described in general formula (I).
As further preferred scheme, aforesaid compound R
1, R
2, R
3, R
4all being selected from the substituent molar percentage of formula (B) structure is more than 85%, and namely four arm compounds (comprise four arm compounds, three arm compounds, two arm compounds, single armed compound and R at mixture
1, R
2, R
3, R
4all be selected from the substituent compound of non-formula (B) structure) in ratio more than 85%, by high performance liquid chromatograph (HPLC), described molar percentage first detects that (determined wavelength is 254nm to mass percent, stationary phase: XDB-C18, moving phase: acetonitrile/water: 5/95 → acetonitrile/water: 95/5), is then calculated by techniques well known and obtains.
As further preferred scheme, aforesaid compound R
1, R
2, R
3, R
4the molar percentage being formula (B) structure substituting group compound is more than 95%, other R
1, R
2, R
3, R
4the molar percentage of appointing 1-3 substituted radical to be selected from compound except formula (B) structure substituting group is less than 2.0%, and namely three arm compounds, two arm compounds, each component of single armed compound molar percentage are in the mixture less than 2.0%.
As further preferred scheme, higly branched chain polymeric drug precursor as shown in the formula (I) or the total apparent relative molecular weight about 20000 of its pharmacy acceptable salt are to about 60000 dalton; Preferably about 35000 to about 45000 dalton.
As further preferred scheme, formula (II-b-1) compound molar percentage is more than 85%, and total apparent relative molecular weight about 20000 is to about 60000 dalton.
As further preferred scheme, formula (II-b-1) compound molar percentage is more than 90%, and total apparent relative molecular weight about 35000 is to about 45000 dalton.
According to proton nmr spectra (
1h-NMR) and techniques well known first determine that one-component is four arms, three arms, two arms or single armed compound respectively, then according to 4 arm polyoxyethylene glycol Glycerol dimers used, (Molecular weights of 4arm poly (ethyleneglycol) (diglycerol) calculates the molecular weight of four arms, three arms, two arms or single armed compound;
Described apparent relative molecular weight always refers to the relative molecular weight of the main mixture containing four arm compounds.Due to the difference of the polymerization degree (n) of 4 arm polyoxyethylene glycol Glycerol dimers used, the apparent relative molecular weight of gained mixture can present different situations, such as, 4ARM (the DG)-PEG-40K that the embodiment of the present invention adopts, namely MW is 40000 daltonian compounds, polymerization degree n can be calculated be about 226.3(to get positive integer be 226), embodiment related substances is as following table:
If adopt MW to be 35000 daltonian 4ARM (DG)-PEG-35K, the molecular weight of aforementioned each component composition and total apparent relative molecular weight corresponding minimizing 5000 dalton of the mixture prepared, in like manner can calculate the asynchronous molecular weight of each substituting group of formula (I) compound.
The present invention provides on the other hand the preparation method of a kind of higly branched chain polymeric drug precursor as shown in the formula (I) or its pharmacy acceptable salt, and it comprises following preparation process:
1) compound 1(camptothecin derivative) react with the amino acid of tertbutyloxycarbonyl protection in the presence of a dehydrating agent, then deprotection obtains compound 2 or its acid salt in acid condition;
2) the compound 3(4 arm polyoxyethylene glycol Glycerol dimer of certain molecular weight) carry out etherification reaction with compound 4 in the presence of a catalyst, then hydrolysis obtains compound 5 in the basic conditions;
3) compound 5 forms compound 6 according to the difference of group A;
4) compound 6 obtains formula (I) compound with compound 2 condensation under condensing agent exists, and its synthetic route is as follows:
Dewatering agent described in step 1) can select esterification to commonly use dewatering agent, preferred DCC, DIC, EDC.HCl, also can operate with other enzymatic synthesis conditions, and such as, refluxing toluene steams moisture or adds molecular sieve etc.; Described acid can be selected from laboratory and commonly use organic acid or mineral acid, such as conventional organic acid is trifluoroacetic acid, trichoroacetic acid(TCA), methylsulfonic acid, trifluoromethanesulfonic acid, tosic acid etc., and conventional mineral acid is hydrochloric acid, Hydrogen bromide, hydrofluoric acid, hydroiodic acid HI, sulfuric acid or phosphoric acid etc.
Step 2) in etherification reaction used catalyst be selected from the acidic substance such as sulfuric acid, sulfonic acid, methylsulfonic acid; Described alkaline condition refers to the solution formed by mineral alkali, and common is sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium-acetate or its aqueous solution etc. combined.
Condensing agent described in step 4) is selected from DIC, DCC, HOBt, EDC.HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or its combination.
As further preferred scheme, when A is
form formula (II) compound, its preparation method is as follows:
Or,
Above-mentioned four-step reaction also first can react, after halo and/or according to R with compound 7' with compound 5
7, R
8definition different switching become corresponding group, its preparation method is as follows:
X, Y are selected from halogen or hydrogen independently of one another, but are asynchronously hydrogen.
As further preferred scheme, the preparation method of formula (II-b-1) compound is as follows:
As further preferred scheme, when A is
time, the preparation method of formula (III) compound is as follows:
The present invention provides a kind of pharmaceutical composition on the other hand, and it comprises the higly branched chain polymeric drug precursor as shown in the formula (I) or its pharmacy acceptable salt and pharmaceutically useful carrier for the treatment of effective dose.
Higly branched chain polymeric drug precursor as shown in the formula (I) or its pharmacy acceptable salt, foregoing pharmaceutical composition can be widely used in the medicine for the preparation of disease relevant to topoisomerase I in treatment mammalian subjects; Especially for the preparation of the application in the medicine for the noumenal tumour in mammalian subjects.
Medicine after PEG modifies, compared with before modification, has following features: the solvability of (1) medicine significantly improves; (2) Increased Plasma Half-life; (3) maximum plasma concentration reduces, and blood concentration fluctuation is less; (4) enzyme degradation reduces, and immunogenicity and antigenicity reduce; (5) toxicity reduces.
Accompanying drawing explanation
Fig. 1 is embodiment step 7 product (PEG-FL118) HPLC spectrogram;
Fig. 2 is the pharmacokinetics correlation curve of PEG-FL118 and FL-118.
Embodiment
Detailed description of the invention: unless stated to the contrary, following use term in the specification and in the claims has following implication.
" C
1-8alkyl " refer to the straight chained alkyl and the containg branched alkyl radical that comprise 1 to 8 carbon atom, alkyl refers to saturated aliphatic hydrocarbon group.Such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group or its various branched chain isomers etc.
Alkyl can be replacement or unsubstituted, and when substituted, substituting group can be substituted on any spendable tie point, is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" cycloalkyl " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, " C
3-8cycloalkyl " refer to the cycloalkyl comprising 3 to 8 carbon atoms, " 5-7 unit cycloalkyl " refers to the cycloalkyl comprising 5 to 7 carbon atoms, such as:
The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.
Polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring." spiro cycloalkyl group " refers to the polycyclic moiety sharing a carbon atom (title spiro atom) between monocycle, and these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group by the number according to sharing spiro atom between ring and ring, and the non-limiting example of spiro cycloalkyl group comprises:
" cycloalkyl " refers to that each ring in system and other rings in system share the full carbon polycyclic moiety of a pair carbon atom adjoined, and wherein one or more rings can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl according to the number of makeup ring, the non-limiting example of cycloalkyl comprises:
" bridge ring alkyl " refers to that any two rings share the full carbon polycyclic moiety of two carbon atoms directly do not connected, and these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Can be divided into dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl according to the number of makeup ring, the non-limiting example of bridge ring alkyl comprises:
Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring wherein linked together with precursor structure is cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.
Cycloalkyl can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" heterocyclic radical " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, wherein one or more annular atomses be selected from nitrogen, oxygen or S (O) r(wherein r be integer 0,1,2) heteroatoms, but do not comprise the loop section of-O-O-,-O-S-or-S-S-, all the other annular atomses are carbon." 5-7 unit heterocyclic radical " refers to the cyclic group comprising 5 to 7 annular atomses, and " 3-8 unit heterocyclic radical " refers to the cyclic group comprising 3 to 8 annular atomses.
The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc.
Polycyclic naphthene base comprises the heterocyclic radical of volution, condensed ring and bridged ring." spiro heterocyclic radical " refers to share the polycyclic heterocyclic group of an atom (title spiro atom) between monocycle, wherein one or more annular atomses be selected from nitrogen, oxygen or S (O) r(wherein r be integer 0,1,2) heteroatoms, all the other annular atomses are carbon.These can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals by the number according to sharing spiro atom between ring and ring.The non-limiting example of spiro cycloalkyl group comprises:
" fused heterocycle base " refers to that each ring in system and other rings in system share the polycyclic heterocyclic group of a pair atom adjoined, one or more ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated, wherein one or more annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) r (wherein r is integer 0 to 2), and all the other annular atomses are carbon.Can be divided into dicyclo, three rings, Fourth Ring or many rings fused heterocycloalkyl according to the number of makeup ring, the non-limiting example of fused heterocycle base comprises:
" bridge heterocyclic radical " refers to that any two rings share the polycyclic heterocyclic group of the atom that two directly do not connect, these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated, wherein one or more annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) r (wherein r is integer 0,1,2), and all the other annular atomses are carbon.Can be divided into dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl according to the number of makeup ring, the non-limiting example of bridge ring alkyl comprises:
Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring wherein linked together with precursor structure is heterocyclic radical, and non-limiting example comprises:
Heterocyclic radical can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" aryl " refers to full carbon monocycle or fused polycycle (namely sharing the right ring of adjacent carbon atoms) group, has many rings (namely it is with the ring of the phase adjacency pair carbon atom) group of the π-electron system of conjugation, " C
5-10aryl " refer to containing 5-10 carbon full carbon aryl, " 5-7 unit aryl " refers to the full carbon aryl containing 5-7 carbon, such as phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:
Aryl can be replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" heteroaryl " refers to comprise 1 to 4 heteroatomic heteroaromatic system, described heteroatoms comprises the heteroatoms of nitrogen, oxygen and S (O) r (wherein r is integer 0,1,2), 5-7 unit heteroaryl refers to the heteroaromatic system containing 5-7 annular atoms, 5-10 unit heteroaryl refers to the heteroaromatic system containing 5-10 annular atoms, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises:
Heteroaryl can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond, C
2-8alkenyl refers to straight chain containing 2-8 carbon or containing branched-chain alkenyl.Such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.
Thiazolinyl can be replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" alkynyl " refers to the alkyl as defined above of at least two carbon atoms and at least one carbon-to-carbon triple bond composition, C
2-8alkynyl group refers to straight chain containing 2-8 carbon or containing branch alkynyl.Such as ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.
Alkynyl can be replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" alkoxyl group " refers to-O-(alkyl), and wherein the definition of alkyl is described above.C
1-8alkoxyl group refers to the alkyl oxy containing 1-8 carbon, and non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy etc.
Alkoxyl group can be optional replacement or unsubstituted, and when substituted, substituting group, is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" cycloalkyloxy " refers to and-O-(unsubstituted cycloalkyl), and wherein the definition of cycloalkyl is described above.C
3-8cycloalkyloxy refers to the cycloalkyl oxy containing 3-8 carbon, and non-limiting example comprises ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
Alkoxyl group can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, sulfydryl, cyano group, nitro, azido-, C
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced.
" halogen " refers to fluorine, chlorine, bromine or iodine.
"-S (O) rR
12" refer to R
12the sulphur, sulfinyl, the sulfonyl that replace.
"-C
1-8-S (O) rR
12" refer to R
12the C replaced
1-8alkyl sulfide, C
1-8alkylsulfinyl, C
1-8alkyl sulfide acyl group.
"-C (O) R
12" refer to R
12the carbonyl replaced.
"-C
1-8-C (O) R
12" refer to R
12the C replaced
1-8alkyl-carbonyl.
"-C (O) OR
12" refer to R
12the ketonic oxygen base replaced.
"-C
1-8-C (O) OR
12" refer to R
12the C replaced
1-8alkyl-carbonyl oxygen base.
"-O-C (O) R
12" refer to R
12the oxygen base carbonyl replaced.
"-C
1-8-O-C (O) R
12" refer to R
12the C replaced
1-8alkyloxycarbonyl.
"-NR
13r
14" refer to R
13, R
14the amino replaced.
"-C
1-8-NR
13r
14" refer to R
13, R
14the C replaced
1-8alkylamino.
"-C (O) NR
13r
14" refer to R
13, R
14the amido replaced.
"-C
1-8c (O) NR
13r
14" refer to R
13, R
14the C replaced
1-8alkyl amido.
"-N (R
12)-C (O) R
12" refer to R
12substituted-amino acyl group.
"-N (R
12)-C (O) OR
12" refer to R
12substituted-amino acyloxy.
"-NH-NR
13r
14" refer to R
13, R
14the diazanyl replaced.
The Chinese of the abbreviation correspondence of the various condensing agent of table 1.
| Be called for short | Chinese |
| DIC | N, N-DIC |
| DCC | N, N-dicyclohexylcarbodiimide |
| HOBT | I-hydroxybenzotriazole |
| EDC.HCl | 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride |
| PyBOP | Phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl |
| PyBroP | Tripyrrole Wan base phosphonium bromide hexafluorophosphate |
| HATU | 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester |
| HCTU | 6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester |
| DEPBT | 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4-ketone |
| EEDQ | 2-oxyethyl group-1-ethoxy carbonic acyl radical-1,2-dihydroquinoline |
| CDI | Carbonyl dimidazoles |
" difunctional connection base " refers to amino-acid residue, amino acid whose amino has lacked a hydrogen, carboxyl has lacked a hydroxyl, and such as glycine residue is "-NH-CH
2-CO-".
" optionally " or " optionally " mean subsequently described ground event or environment can but need not occur, this explanation comprises this event or environment occurs or not spot occasion.Such as, " optionally by heterocyclic group that alkyl replaces " mean alkyl can but must not exist, this explanation comprises situation that heterocyclic group replaced by alkyl and heterocyclic group not by situation that alkyl replaces.
" replacement " refers to the one or more hydrogen atoms in group, is preferably maximum 5, is more preferably 1 ~ 3 hydrogen atom and is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group is only in their possible chemical position, those skilled in the art can determine when not paying and too much making great efforts (by experiment or theoretical) may or impossible replacement.Such as, have the amino of free hydrogen or hydroxyl and the carbon atom with unsaturated (as olefinic) key in conjunction with time may be unstable.
" pharmaceutical composition " represent containing on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components such as physiology/pharmaceutically useful carrier and vehicle.The object of pharmaceutical composition promotes the administration to organism, is beneficial to the absorption of activeconstituents and then plays biological activity.
Be used for further describing the present invention below in conjunction with embodiment, but these embodiments not limit scope of the present invention.
The compounds of this invention structure by nucleus magnetic resonance (NMR) or/and LC-MS chromatogram (LC-MS) is determined.NMR displacement (δ) provides with the unit of 1,000,000/(ppm).The mensuration of NMR uses BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d
6), deuterochloroform (CDCl
3), deuterated methanol (CD3OD), be inside designated as tetramethylsilane (TMS).
The mensuration Agilent1200Infinity Series mass spectrograph of LC-MS chromatogram LC-MS.The mensuration of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 × 4.6mm chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) uses adopts is 0.15mm ~ 0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm.
Column chromatography generally uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.
Known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, splendid far away chemistry science and technology (Accela ChemBio Inc), reach the companies such as auspicious chemical.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects argon gas or the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.
Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.
Microwave reaction uses Anton Paar Monowave300 type microwave reactor.
Without specified otherwise in embodiment, react and carry out under nitrogen atmosphere or argon atmospher.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum temperature of reaction, is 20 DEG C ~ 30 DEG C.
The monitoring of the reaction process in embodiment adopts tlc (TLC), and the system of reacting the developping agent used has: methylene dichloride and methanol system, normal hexane and ethyl acetate system, and the volume ratio of solvent regulates according to the polarity difference of compound.
The system of eluent of the column chromatography that purifying compounds adopts and the developping agent system of tlc comprise: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system.The volume ratio of solvent is different and regulate according to the polarity of compound, also can add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent regulates.
4 arm polyoxyethylene glycol Glycerol dimers (4arm poly (ethylene glycol) (diglycerol)) are purchased from JenkemTechnology.Embodiment of the present invention employing 4ARM (DG)-PEG-40K i.e. MW is the compound of 40000 dalton (polymerization degree n is about 226) is raw material.
embodiment
Step one:
Compound 2-1(5g is added, 0.026mol, 1.0 equivalents in 500mL round-bottomed flask), iron powder (4.30g, 0.078mol, 3.0 equivalents), ammonium chloride (6.96g, 0.13mol, 5.0 equivalents), water (150mL) and methyl alcohol (50mL), N
2the lower backflow of protection 2 hours.It is complete that LC-MS monitors feedstock conversion, stopped reaction, is cooled to room temperature, filters, filter cake ethyl acetate is washed, separatory, aqueous phase is extracted with ethyl acetate (30mL × 5), merges organic phase, organic phase anhydrous sodium sulfate drying, filter, be spin-dried for, crude product uses column chromatography (sherwood oil: ethyl acetate: 5:1).2.0g, yellow solid, yield 50%.
ESI:m/e
+:166[M+H
+].
Step 2:
Add compound 1-1(0.15g, 0.57mmol in 25mL single port flask, 1.0 equivalents) and acetic acid (4mL), be heated to 80 degree under nitrogen protection, under 80 degree, drip compound 2-2(0.122g, 0.74mmol, 1.3 equivalents) toluene (4mL) solution.Heated overnight under a nitrogen, after reaction terminates, is cooled to room temperature, and filter, filter cake washing with acetone, dry air obtains yellow solid.0.15g, productive rate: 67%.
ESI:m/e
+:393[M+H
+].
1H-NMR[DMSO,400MHz]:δ8.47(s,1H),7.52(s,2H),7.25(s,1H),6.50(s,1H),6.29(s,2H),5.41(s,2H),5.22(s,2H),1.82-1.90(m,2H),0.88(t,J=7.2Hz,3H).
Step 3:
Compound 1-2(52mg is added, 0.13mmol, 1.0 equivalents in 50mL reaction flask), N-tert.-butoxy glycine (58mg, 0.33mmol, 2.5 equivalents), anhydrous methylene chloride 50mL, stirs under ice bath.Reaction solution stirs 10 minutes under ice bath, then adds DMAP(16mg, 0.39mmol, 1.0 equivalents) and DCC(80mg, 0.39mmol, 3.0 equivalents).Then room temperature reaction spends the night, stopped reaction.Filter, filtrate is washed with saturated sodium bicarbonate solution washing (10mL × 1), salt solution (10mL × 2), organic phase anhydrous sodium sulfate drying, filter, vacuum rotary steam, the large plate of crude product is separated (methylene dichloride: methyl alcohol: V/V25:1), 32mg, faint yellow solid, yield 45%.
ESI:m/e
+:550[M+H
+].
Step 4:
Compound 1-3(40mg is added, 0.07mmol, 1.0 equivalents in 50mL reaction flask), methylene dichloride (10mL), stirs under ice bath.Drip trifluoroacetic acid (1mL) under ice bath, stirring at room temperature one hour, it is complete that LC-MS monitors feedstock conversion, and be spin-dried for, crude product is directly used in next step.Obtain 35mg yellow oil, yield 100%.
Step 5:
Compound 3-1 (3.125g, 0.078mmol, 1.0 equivalents) is added, toluene (60mL), N in 100mL there-necked flask
2the lower azeotropic water removing of protection.After drying terminates, system is cooled to 30 degree, then potassium tert.-butoxide (105mg is dripped, 0.936mmol, 12 equivalents) t-butanol solution (2mL), stir half an hour, then drip bromo-acetic acid tert-butyl (0.24g, 1.248mmol, 16 equivalents), stirring one hour under 30 degree, reaction end is cooled to 25 degree.Drip ether (40mL), separate out white solid, filter, white solid washed with diethylether, solid uses dichloromethane solution again, then drips ether (90mL), separates out white solid, and filter, washed with diethylether, dry air obtains white solid.3.0g, yield 96%.
Step 6:
Compound 3-2 (1.20g, 0.03mmol, 1.0 equivalents) is added in 50mL single port bottle, anhydrous methylene chloride (12mL), stirs under ice bath, then under ice bath, drips trifluoroacetic acid (6mL), stirring at room temperature three hours, after reaction terminates, is spin-dried for.Residue methylene dichloride (6mL) dissolves, and drips ether, and white solid is separated out, and filters.Solid sodium hydrogen carbonate solution dissolves (5mL, 0.5%NaHCO
3), dichloromethane extraction (15mL × 2), merges organic phase, organic phase anhydrous sodium sulfate drying, and filter, be spin-dried for, crude product methylene dichloride dissolves, and drips ether and separates out white solid, filter, solid then with anhydrous diethyl ether washing, dry white solid.0.70g, yield 58%.
1H-NMR[CDCL
3,400MHz]:δ4.15(s,1H),3.47-3.81(m,415H).
Step 7:
Compound 3-3(124mg is added, 0.0031mmol, 1.0 equivalents) in 100mL single port flask; anhydrous methylene chloride (10mL), nitrogen protection, stirs under ice bath; compound 1-4(35mg is added, 0.062mmol, 20 equivalents) under ice bath; PPAC(130mg, the ethyl acetate solution of 50 % by weight, 0.409mmol; 132 equivalents); DMAP(38mg, 0.31mmol), stirred overnight at room temperature.After reaction terminates, be spin-dried for, crude product gel column is separated.Faint yellow look solid PEG-FL118, the concrete outcome of 90mg, purity 95%(HPLC see Fig. 1, stationary phase: XDB-C18, moving phase: acetonitrile/water: 5/95 → acetonitrile/water: 95/5), productive rate 70%.
1H-NMR[CDCl
3,400MHz]:δ8.48(s,1H),8.19(t,J=6.0Hz,1H),7.52(s,1H),7.47(s,1H),7.04(s,1H),6.29(s,2H),5.47(s,2H),5.23(s,2H),4.15-4.21(m,1H),4.05-4.11(m,1H),3.92(s,2H),3.47-3.69(m,1120H),2.11-2.17(m,2H),0.90(t,J=7.2Hz,3H).
evaluated biological activity
One, PEG-FL118 antiproliferative effect active testing
The cell assay in vitro of the following stated can be used to measure the proliferation inhibition activity of the compounds of this invention for cancer cells, its active available IC
50value represents.FL-118 entrained by PEG-FL118 is the inhibitor of a kind of DNA topoisomerase-I, has lethal effect to multiple cancer cells; We compare the proliferation inhibition activity of PEG-FL118 and FL118 to cancer cells.
The general approach of this type of test is as follows: first select multiple different cancerous cell line (being purchased from Institute ofbiochemistry and cell biology), with suitable cell concn (such as, 5000 cell/mL nutrient solutions) be seeded on 96 well culture plates, the test-compound solution of a series of gradient concentrations (general 8 to 10 concentration) with substratum dilution is added, cultured continuously 72 hours subsequently to each hole.After 72 hours, available cells counting reagent kit (
luminescent Cell Viability Assay, is purchased from Promega) method measures the activity of compound antiproliferative effect.IC
50value is by under a series of different concns, and the suppression numerical value of test-compound on cell proliferation calculates.
The biochemical activity of the compounds of this invention is measured by above test, the IC recorded
50value sees the following form.
The various cancer cell multiplication of conclusion: PEG-FL118 all has obvious inhibit activities, suitable with the cancer cell multiplication inhibit activities of FL-118.
pharmacokinetic Evaluation
Two, the pharmacokinetics test of PEG-FL118
1, make a summary
Take rat as animal subject, application HPLC method determines the FL-118 drug level that rat vein gives after PEG-FL118 or FL-118 compound in different time blood plasma.The pharmacokinetics behavior of research PEG-FL118 compound in rat body, evaluates its Pharmacokinetic Characteristics.
2, testing program
2.1 test drug
PEG-FL118 and FL-118 compound
2.2 experimental animal
Healthy adult SD rat 6, male, be divided into 2 groups, often organize 3, purchased from Shanghai Slac Experimental Animal Co., Ltd..
2.3 Pharmaceutical formulations
PEG-FL-118: take a certain amount of medicine, adds normal saline and becomes 5.3614mg/ml solution.
FL-118: take a certain amount of medicine, dimethyl sulfoxide (DMSO) makes dissolving (the final content of dimethyl sulfoxide (DMSO) is 5%), adds 0.25% hydroxypropyl-beta-cyclodextrin and is mixed with 0.2mg/mL solution.
2.4 administration
SD Rat Fast spends the night posterior vein administration, and administration volume is 5.0mL/kg.The dosage of PEG-FL-118 is the dosage of 26.807g/kg, FL-118 is 1mg/kg; Under this dosage, both volumetric molar concentrations are identical.
3, operate
Rat vein administration PEG-FL118 compound, before administration and after administration 5 minutes, 15 minutes, 0.5,1.0,2.0,3.0,6.0,24.0,48.0,72.0,96.0,154.0 hours jugular vein blood collection 0.3ml, are placed in heparinised tubes, 4 DEG C, 6000 revs/min centrifugal 5 minutes separated plasmas, in-80 DEG C of preservations, feed in 2 hours after administration.
Rat vein administration FL118 compound, before administration and after administration 5 minutes, 15 minutes, 0.5,1.0,2.0,3.0,6.0,24.0 hours jugular vein blood collection 0.3ml, be placed in heparinised tubes, 4 DEG C, 6000 revs/min centrifugal 5 minutes separated plasmas, in-80 DEG C of preservations, feed in 2 hours after administration.
FL-118 concentration after the medical intravenous administration of mensuration different concns in rat plasma: the rat plasma 80 μ L in each moment after drawing medicine, add the acetonitrile solution that 160 μ L contain interior mark FL-118 and 0.5% acetic acid, vortex mixed 1 minute, 4 DEG C centrifugal 10 minutes (13000 revs/min), get supernatant liquor 10 μ L and carry out LC/MS/MS.
4, pharmacokinetic parameter result
FL-118 pharmacokinetic parameter after PEG-FL118 and FL-118 administration is as follows:
Conclusion: compared with direct injection FL-118, transformation period and the AUC of the FL-118 of PEG-FL118 generation are high a lot of times, significantly reduce clearance rate, have obvious pharmacokinetic advantage.
Finally should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted the present invention, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
Claims (29)
1. there is higly branched chain polymeric drug precursor or its pharmacy acceptable salt of formula (I) structure,
Wherein, A is selected from following structure:
R
1, R
2, R
3, R
4be selected from hydroxyl, sulfydryl, C independently of one another
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-O-C (O) R
12,-NR
13r
14,-N (R
12)-C (O) OR
12or formula (B) substituting group,
Condition is R
1, R
2, R
3, R
4at least one is selected from formula (B) substituting group;
Wherein said C
1-8alkyl, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl or 5-10 unit heteroaryl are independently optionally selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C by one or more separately further
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced;
R
5, R
6be selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14;
Wherein said C
1-8alkyl, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl or 5-10 unit heteroaryl are independently optionally selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C by one or more separately further
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced;
R
7, R
8, R
9be selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14;
Wherein said C
1-8alkyl, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl or 5-10 unit heteroaryl are independently optionally selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C by one or more separately further
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced;
R
10and R
11be fused into 5-7 unit cycloalkyl, 5-7 unit heterocyclic radical, 5-7 unit's aryl or 5-7 unit heteroaryl with the phenyl be connected, be selected from following structure with the structure that the phenyl be connected is formed jointly:
Wherein 5-7 unit cycloalkyl, 5-7 unit heterocyclic radical, 5-7 unit's aryl or 5-7 unit heteroaryl are optionally selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, azido-, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, C
1-8alkoxyl group, C
1-8alkyl sulfenyl, C
3-8cycloalkyloxy, C
3-8cycloalkylthio, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, 3-8 unit heterocyclic thio, C
5-10aryl, C
5-10aryloxy, C
5-10artyl sulfo, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base, 5-10 unit Heteroarylthio ,-S (O) rR
12,-C
1-8-S (O) rR
12,-C (O) R
12,-C
1-8-C (O) R
12,-C (O) OR
12,-C
1-8-C (O) OR
12,-O-C (O) R
12,-C
1-8-O-C (O) R
12,-NR
13r
14,-C
1-8-NR
13r
14,-C (O) NR
13r
14,-C
1-8c (O) NR
13r
14,-N (R
12)-C (O) R
12,-N (R
12)-C (O) OR
12, or-NH-NR
13r
14substituting group replaced;
R
12, R
13, R
14be selected from hydrogen, C
1-4alkyl;
L is difunctional connection base, is selected from native amino acid residues;
M is 0,1,2;
N is positive integer;
P, q, t are 0,1,2,3 or 4.
2. higly branched chain polymeric drug precursor according to claim 1 or its pharmacy acceptable salt, is characterized in that, difunctional connection base L is selected from L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, glycine, phenylalanine, tryptophan residue; L is preferably from L-Ala or glycine residue.
3. higly branched chain polymeric drug precursor according to claim 1 or its pharmacy acceptable salt, is characterized in that, A is
form formula (II) compound
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
10, R
11, R
12, R
13, R
14, L, m, n, f as claim 1 define.
4. higly branched chain polymeric drug precursor according to claim 3 or its pharmacy acceptable salt, is characterized in that, R
7, R
8when being hydrogen, form formula (II-a) compound:
R
1, R
2, R
3, R
4, R
5, R
6, R
10, R
11, R
12, R
13, R
14, L, m, n, r as claim 1 define, condition is when m is 1, R
5, R
6be asynchronously hydrogen.
5. higly branched chain polymeric drug precursor according to claim 4 or its pharmacy acceptable salt, is characterized in that, R
5, R
6be hydrogen, m be 2, form formula (II-a-1) compound:
R
1, R
2, R
3, R
4, R
10, R
11, R
12, R
13, R
14, L, n, r as claim 1 define.
6. higly branched chain polymeric drug precursor according to claim 5 or its pharmacy acceptable salt, is characterized in that, is selected from formula (II-a-1-1) compound:
N as claim 1 define.
7. higly branched chain polymeric drug precursor according to claim 4 or its pharmacy acceptable salt, is characterized in that, m is 1, R
5, R
6one of be selected from hydrogen, another is selected from methyl, forms formula (II-a-2) compound:
R
1, R
2, R
3, R
4, R
10, R
11, R
12, R
13, R
14, L, n, r as claim 1 define.
8. higly branched chain polymeric drug precursor according to claim 7 or its pharmacy acceptable salt, is characterized in that, is selected from formula (II-a-2-1) compound:
N as claim 1 define.
9. higly branched chain polymeric drug precursor according to claim 1 or its pharmacy acceptable salt, is characterized in that, A is
m is 1, R
5, R
6, R
7, R
8be hydrogen simultaneously, form formula (II-b) compound:
R
1, R
2, R
3, R
4, R
10, R
11, R
12, R
13, R
14, L, n, r as claim 1 define.
10. higly branched chain polymeric drug precursor according to claim 9 or its pharmacy acceptable salt, is characterized in that, is selected from formula (II-b-1) compound:
N as claim 1 define.
11. higly branched chain polymeric drug precursor according to claim 1 or its pharmacy acceptable salts, it is characterized in that, A is
form formula (III) compound:
R
1, R
2, R
3, R
4, R
5, R
6, R
9, R
10, R
11, R
12, R
13, R
14, L, m, n, p, q, t, r as claim 1 define.
12. higly branched chain polymeric drug precursor according to claim 11 or its pharmacy acceptable salts, it is characterized in that, m is 1, forms formula (III-a) compound:
R
1, R
2, R
3, R
4, R
5, R
6, R
9, R
10, R
11, R
12, R
13, R
14, L, n, p, q, t, r as claim 1 define.
13. higly branched chain polymeric drug precursor according to claim 12 or its pharmacy acceptable salts, is characterized in that, R
5, R
6be hydrogen, form formula (III-a-1) compound:
R
1, R
2, R
3, R
4, R
9, R
10, R
11, R
12, R
13, R
14, L, n, p, q, t, r as claim 1 define.
14. higly branched chain polymeric drug precursor according to claim 13 or its pharmacy acceptable salts, is characterized in that, are selected from formula (III-a-1-1) compound:
Or formula (III-a-1-2) compound:
Or formula (III-a-1-3) compound:
N as claim 1 define.
15. higly branched chain polymeric drug precursor according to claim 11 or its pharmacy acceptable salts, is characterized in that, m is 0 or 2, R
5, R
6be hydrogen, form formula (III-b) compound:
R
1, R
2, R
3, R
4, R
9, R
10, R
11, R
12, R
13, R
14, L, n, p, q, t, r as claim 1 define.
16. higly branched chain polymeric drug precursor according to claim 11 or its pharmacy acceptable salts, it is characterized in that, p is 0, forms formula (III-c) compound:
R
1, R
2, R
3, R
4, R
5, R
6, R
10, R
11, R
12, R
13, R
14, L, m, n, q, t, r as claim 1 define.
17. higly branched chain polymeric drug precursors according to any one of claim 1 to 16 or its pharmacy acceptable salt, is characterized in that, R
1, R
2, R
3, R
4all being selected from the substituent molar percentage of formula (B) structure is more than 85%.
18. higly branched chain polymeric drug precursor according to claim 17 or its pharmacy acceptable salts, is characterized in that, R
1, R
2, R
3, R
4the molar percentage being formula (B) structure substituting group compound is more than 95%, other R
1, R
2, R
3, R
4the molar percentage of appointing 1-3 substituted radical to be selected from compound except formula (B) structure substituting group is less than 2.0%.
19. higly branched chain polymeric drug precursors according to any one of claim 1 to 17 or its pharmacy acceptable salt, is characterized in that, the total apparent relative molecular weight about 20000 of prodrug is to about 60000 dalton; Preferably about 35000 to about 45000 dalton.
20. higly branched chain polymeric drug precursor according to claim 10 or its pharmacy acceptable salts, is characterized in that, formula (II-b-1) compound molar percentage is more than 85%, and total apparent relative molecular weight about 20000 is to about 60000 dalton.
21. higly branched chain polymeric drug precursor according to claim 20 or its pharmacy acceptable salts, is characterized in that, formula (II-b-1) compound molar percentage is more than 90%, and total apparent relative molecular weight about 35000 is to about 45000 dalton.
The preparation method of 22. 1 kinds of higly branched chain polymeric drug precursors as shown in the formula (I) or its pharmacy acceptable salt, it comprises following preparation process:
1) compound 1 reacts with the amino acid of tertbutyloxycarbonyl protection in the presence of a dehydrating agent, and then deprotection obtains compound 2 or its acid salt in acid condition;
2) compound 3 carries out etherification reaction with compound 4 in the presence of a catalyst, and then hydrolysis obtains compound 5 in the basic conditions;
3) compound 5 forms compound 6 according to the difference of group A;
4) compound 6 obtains formula (I) compound with compound 2 condensation under condensing agent exists, and its synthetic route is as follows:
23. preparation methods according to claim 22, is characterized in that:
Described in step 1), dewatering agent is selected from DCC, DIC, EDC.HCl; Described acid is organic acid or mineral acid, and described organic acid is selected from trifluoroacetic acid, trichoroacetic acid(TCA), methylsulfonic acid, trifluoromethanesulfonic acid or tosic acid, and described mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydrofluoric acid, hydroiodic acid HI, sulfuric acid or phosphoric acid;
Step 2) in etherification reaction used catalyst be selected from sulfuric acid, sulfonic acid or methylsulfonic acid; Described alkaline condition refers to the solution formed by mineral alkali, and it is selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium-acetate or its aqueous solution combined;
Condensing agent described in step 4) is selected from DIC, DCC, HOBt, EDC.HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or its combination.
24. preparation methods according to claim 22, is characterized in that: when A is
form formula (II) compound, its preparation method is as follows:
or,
Above-mentioned four-step reaction first reacts, after halo and/or according to R with compound 7' with compound 5
7, R
8definition different switching become corresponding group, its preparation method is as follows:
X, Y are selected from halogen or hydrogen independently of one another, but are asynchronously hydrogen.
25. preparation methods according to claim 24, is characterized in that: when A is
form formula (II-b-1) compound, its preparation method is as follows:
26. preparation methods according to claim 22, is characterized in that: when A is
time, form formula (III) compound, its preparation method is as follows:
27. 1 kinds of pharmaceutical compositions, it comprises the higly branched chain polymeric drug precursor according to claim 1 or its pharmacy acceptable salt and pharmaceutically useful carrier for the treatment of effective dose.
28. higly branched chain polymeric drug precursors according to claim 1 or its pharmacy acceptable salt or the application of pharmaceutical composition according to claim 27 in the medicine for the preparation of disease relevant to topoisomerase I in treatment mammalian subjects.
29. higly branched chain polymeric drug precursors according to claim 1 or its pharmacy acceptable salt are for the preparation of the application in the medicine for the noumenal tumour in mammalian subject.
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