JPH03287545A - Target-directing polymeric drug compound and intermediate thereof - Google Patents

Abstract

PURPOSE:To provide a polymeric drug compound holding both a high pharmaceutical activity and a target-directing property without deteriorating the water solubility thereof even when the amount of the drug ingredient is increased, by employing the compound having both hydrophilic segments and a segment bonded to the drug ingredient and the target-directing substance to exhibit a pharmacological function. CONSTITUTION:A polymeric drug compound prepared by bonding a target-directing substance (e.g. antibody or lectin) to the hydrophilic segment-excluding site of a block (or graft) copolymer having both the hydrophilic segment and a pharmacological function segment bonded to the drug ingredient directly or through a bonding chain, e.g. a compound of the formula (l is 1-30; n is 5-400; m is 1-300; x is 0-300; R<1> is OH or the residue of the drug ingredient, at least one of the groups is the residue of the drug ingredient; R<2> is the residue of the target-directing substance; R<3> is CH3, C2H5 or the like; A is a bonding chain originated from a coupling agent employed for the direct or indirect bond reaction. The hydrophilic segment includes polyethylene glycol, PVA, and the component for forming the pharmacological function includes polyasparaginic acid and polylactic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to target-directed polymeric pharmaceutical compounds and intermediates thereof.

More specifically, the first object of the present invention is to connect a site other than the hydrophilic segment of a block (or graft) copolymer having a hydrophilic segment and a pharmacologically functional segment to which a drug is bonded to a target-directing substance (i.e., in vivo). The object of the present invention is to provide a target-directed polymeric pharmaceutical compound which is bound to a substance (having a high affinity for a desired site or component) directly or via a linking chain.

The second object of the present invention is to synthesize a target-directed polymeric pharmaceutical compound comprising a block (or graft) copolymer having a hydrophilic segment and a functional group-bearing segment capable of binding a drug and/or a target-directing substance. The goal is to provide intermediates.

The target-directed polymeric pharmaceutical compound of the present invention is capable of stably binding and retaining a large amount of drug within the molecule, and has the ability to efficiently deliver a large amount of drug to a treatment site or target in the body. It is something that you have.

According to the present invention, even when the drug is a hydrophobic substance, micelles are formed in which the pharmacologically functional segment to which a large amount of the hydrophobic drug is bound is surrounded by hydrophilic segments, that is, hydrophilic polymer chains. A target-directing polymer with excellent properties that stabilizes the binding of drugs and target-directing substances, is solubilized in water at high concentrations, and has almost no antigenicity, which is a problem with polymer drugs. Pharmaceutical compounds are provided.

[Conventional technology]

When manufacturing a target-directed pharmaceutical compound by combining a low-molecular drug and a target-directing substance, attempts are made to prevent functional decline due to the binding of both components by binding both components using a polymer chain as an intermediate support. Several attempts have been made to bind large amounts of drugs without impairing the water solubility of the desired target-directed pharmaceutical compound.

However, the polymer chains used in previous attempts were homopolymers consisting of a single component or polymers of two components alternately or in random order, and the targets manufactured using these polymer chains were Directed pharmaceutical compounds have not always been satisfactory as pharmaceuticals.

[Problem to be solved by the invention]

Conventional target-directed polymeric pharmaceutical compounds produced using polymer chains as intermediate supports have the disadvantage that water solubility decreases when the amount of hydrophobic drug supported is increased in order to increase drug efficacy.

The object of the present invention is to solve the conventional drawbacks by using a polymer chain with a new structure in place of the conventional polymer chain, and to achieve high drug efficacy without decreasing the water solubility even when the amount of drug supported is increased. Another object of the present invention is to provide a target-directed polymeric pharmaceutical compound that maintains target directivity.

As a result of various studies to find a polymer chain with a novel structure that meets the above objectives, the present inventors have discovered a segment that binds drugs and target-directing substances and exhibits pharmacological functions, and a segment that binds drugs and target-directing substances. The present invention was completed based on the discovery that a block (or graft) copolymer having a hydrophilic segment to which no substance is bonded has very excellent properties.

[Means to solve the problem] The present invention includes the following inventions.

1. A block (or graft) copolymer having a hydrophilic segment and a pharmacologically functional segment to which a drug is attached has a site other than the hydrophilic segment and a targeting substance (i.e., has a high affinity for a desired site or component in the body). A target-directed polymeric pharmaceutical compound formed by bonding a substance (substance) directly or via a linking chain.

2. General formula (I) (wherein l is 1 to 30, n is 5 to 400, a is 1 to 30
0, , R1 represents a target-directing substance residue, R3 to CHs, CtHs, etc., and A represents a binding chain resulting from direct binding or a coupling agent used in the binding reaction. ) The target-directed polymeric pharmaceutical compound according to 1 above.

3. The target-directed polymeric pharmaceutical compound according to item 1 or 2 above, wherein the target-directed substance is an antibody.

4. Items 1 to 3 above, characterized in that the drug is an anticancer drug.
Targeting polymeric pharmaceutical compounds as described.

5. The bonding chain A resulting from the coupling agent has the formula (n) CO
CFlzCtbSSCf(zcHzcO-...(II
) The target-directed polymeric pharmaceutical compound as described in 2 to 4 above, which is a divalent chain compound residue represented by:

6. The target-directing polymeric pharmaceutical compound as described in 2 to 5 above, wherein the bond between the target-directing substance residue R2 and the binding chain A is an amide bond.

7. The target-directed polymeric pharmaceutical compound as described in 4 to 6 above, wherein the anticancer agent is adriamycin.

8. An intermediate for synthesizing a target-directed polymeric pharmaceutical compound comprising a block (or graft) copolymer having a hydrophilic segment and a functional group-bearing segment capable of binding a drug and/or a target-directing substance.

9, General formula (III) R”40 C) I z CFig+i-NH(COC
FIN)I 謄hoCOCHHz C)I N LiverZ
CH, COY COY ---(III) (wherein, n is 5 to 400, m is 1 to 300, x is zero or an integer of 1 to 300, and Y is the same or different and OH
and drug residues, and R3 is C)+3. 8. The intermediate for synthesizing a target-directed polymeric pharmaceutical compound as described in 8 above, which is made of a block copolymer m-conductor represented by CJS or the like.

In the present invention, examples of the hydrophilic segment include polyethylene glycol, polysancharide, polyacrylamide, and polymethacrylic acid.

Polyvinylpyrrolidone, polyvinyl alcohol polymethacrylate, polyacrylate, polyamino acid, etc. or derivatives thereof can be used.

Components that combine with drugs to form pharmacologically functional segments include polyaspartic acid, polyglutamic acid, polylysine, polyacrylic acid, polymethacrylic acid, polymalic acid, polylactic acid, polyalkylene oxide, long-chain alcohols, etc., or derivatives thereof. is available.

Examples of drugs include anticancer drugs such as adriamycin, downmycin 1 methotrexate, and mitomycin C, drugs for the central nervous system, drugs for the peripheral nervous system, drugs for allergy,
Cardiovascular rack 5 respiratory system drugs, digestive system drugs, hormone drugs 1 metabolic drugs.

Antibiotics, chemotherapy drugs, etc. can be used.

Targeting substances include poly(or mono)clonal antibodies derived from warm-blooded animals or humans, lectins, polysaccharides, monosaccharides, transferrin, etc. that have high affinity for desired sites or components in living organisms. Substances are available.

The linkage between the targeting agent and the copolymer can be formed directly or via a linking chain, for example 2-iminothiolene, n-succinidyl 3-(2-pyridylthio)propionate (SPDP).

A coupling agent such as succinimidyl 4-(P-maleimidophenyl)butyrate can be used, or a bond can be formed between reducing disulfide groups, maleimide groups, etc.

Below, a block copolymer having a hydrophilic segment derived from polyethylene glycol and a pharmacologically functional segment derived from polyaspartic acid bound with the anticancer drug Adriamycin as a drug, and a human-derived immunoglobulin G
The present invention will be described in detail by taking as an example a target-directed polymeric pharmaceutical compound formed by binding an antibody (antibody) using a coupling agent (SPDP). A schematic structural diagram of this target-directed polymeric drug compound is shown in FIG.

The base of this compound is β-
Benzyl L-aspartate N-carboxylic anhydride (
BLA-NCA) is polymerized using a polyethylene glycol (molecular weight 250 to 18,000) having an alkoxy group such as a methoxy group at one end and a primary amino group at one end as an initiator to form a polyethylene glycol poly(β-benzyl L-aspartate) block. Copolymer (PEG-PBLA)
This PEG-PBLA is then subjected to alkaline hydrolysis to obtain a polyethylene glycol-polyaspartic acid block copolymer (PEG-P(Asp)). 80% of this PEG-P(Asp) aspartic acid residue is converted to β-ade during alkaline hydrolysis.

The terminal primary amino group of this PEG-P (Asp) is reacted with a coupling agent (SPDP) to form a pyridyldithiopropionyl group (FDP), which is a functional group for coupling.
) to obtain an intermediate of the present invention (PEG-P(Asp)-FDP) in which Y in formula (m) is OHO. By adding the anticancer drug adriamycin (ADJ?I) and water-soluble carbodiimide (EDC) to this intermediate, an amide bond is formed between the primary amino group of adriamycin and the carboxyl group of polyaspartic acid (III). The intermediate of the present invention in which Y in the formula is a drug residue (PEG-P[As
p(ADR)]-PDP).

The intermediate into which this drug was introduced was dithiothreitol (DT
T) to cleave the 15S-bond of the FDP chain to form 15H, and then add a camping agent (SPDP) in advance.
A pyridyldithiopropionyl group was introduced into the target inventive polymeric pharmaceutical compound (PEG-P[Asp(ADR )] IgG
).

The molecular weight of the polyaspartic acid (P (Asp)) portion of the compound of the present invention that is filtered through L in this way is 116 to 3.
5.000, and the substitution rate of adriamycin (relative to aspartic acid residues) is P (Asp
) has a molecular weight of 12 to 33 mo1% when the molecular weight is 1900, and 3 to 37 mo1% when the molecular weight is 10,000.

The number of adriamycin-carrying block copolymers introduced per immunoglobulin G1 molecule is on average 0.3 to 2.
I've gotten up to 5 items.

In all cases, the compounds of the present invention that have bottomed out have good water solubility despite the high adriamycin substitution rate, and can be freeze-dried or concentrated (adriamycin equivalent 2
The water solubility was maintained even at 0.0%/d).

In addition, in the compound of the present invention, the disulfide bond in the bonding chain between the block copolymer and the antibody was significantly stabilized against a reducing agent compared to a normal disulfide bond.

These reasons are because the compound aggregates in an aqueous solution as micelles in which the adriamycin binding site and disulfide bonding site in the molecule are surrounded by polyethylene glycol chains, and as a result, the water solubility of the compound is maintained and This is because the disulfide bonds were sterically protected from attack by the reducing agent.

This was shown because adriamycin-based fluorescence was quenched by microaggregation.

(Example) Examples will be shown below to explain the present invention in more detail. In the following explanation, the numbers in parentheses after the compound core or compound abbreviation indicate the compound number in FIG. 2 showing the synthesis procedure of the compound of the present invention.

1. β-benzyl L-aspartate N-carboxylic acid anhydride (BLA-NCA) (2) 7.21g of N,N
-Dissolved in dimethylformamide (DMF) 12-,
Add 60d of chloroform. Polyethylene glycol with methoxy group on one end and amino group on the other end (molecular weight 4300)
(I) Dissolve 6,00g in chloroform 60- and add the solution to the BLA-NCA solution. After 70 hours, the reaction mixture was added dropwise to diethyl ether in Step 21, and the precipitated polymer was collected by filtration, washed with diethyl ether, and dried in vacuum to form a polyethylene glycol-poly(β-benzyl L-aspartate) block. A copolymer (PEG-PBLA) (3) is obtained. Yield 10
．． 09g (84%).

Dissolve 10.03 g of PEG-PBLA (3) in 100-chloroform. Water: methanol: l-propanol = 1:1:2 (volume ratio) with 0.4 sodium hydroxide
PEG-PBLA?3Ni9 alkali mixture? W
Add to liquid.

The amount of alkali added was set to be 1.5 times the equivalent of the benzyl ester of the PBLA portion. After stirring for 110 minutes, add dropwise to the separated diethyl ether. Filter the precipitated polymer, dissolve it in distilled water of 201d, and add it dropwise to the separated diethyl ether.
Dialyze in water for 39 hours using ctrapor 7 dialysis membrane (molecular weight fraction = 1000). The solution in the membrane was freeze-dried to form polyethylene glycol-polyaspartic acid block copoly7-(PEG-P(^3p)) (4a)
get. Yield 3.94g (49%).

Proton NMR measurements revealed that there were 17 aspartic acid residues in each block copolymer chain.

PEG-P (Asp) block copolymer (4a) 1
．． Dissolve 022 g in 200 d of pH 9,5,0,1N sodium borate buffer. N~succinimidyl 3-(2-
Pyridylthio)propionate (SPDP) 1.02
1 g dissolved in 10-DMF was added to the solution (4a) in two equal amounts at room temperature for 10 minutes.

10 minutes after the second addition, the reaction solution was dialyzed overnight in distilled water (using a Spectrabore 7 molecular weight cut 1000 dialysis membrane), and then gelled in distilled water using a column packed with Sephadex G-25 gel. Filtered and lyophilized. Yield 523.1■ (yield 51%).

The 3-(2
-Pyridyldithio)propionyl M (FDP) was quantified by the absorption at 343 nm of 2-pyridinethione released upon reduction with 50mM dithiothreitol, and it was found that FDP was introduced at 20% of the terminals. Ta.

(PEG-P(Asp)-PDP) obtained here
Lycium volimer (4b) 523.1mg was added to 0.1N phosphorus-Ml buffer (pH 7,50, containing 1M NaCl) (P
BS) 5-, 77.4 mg of 14-dithiothreitol was dissolved in water 1- and added thereto, and the mixture was heated at room temperature for 20 minutes.
The reaction was carried out for 1 minute to reduce the S--S bond in the PDP chain at the end of the block copolymer to -5H.

After the reduction reaction, dialysis (Spectrabore 7, molecular weight cutoff 10)
00 membrane in distilled water) and then gel filtration (Sephadex G-25, in distilled water) to remove low molecular weight substances, which was passed through a gel column of thiopropyl Sepharose 6B (55d, in PBS), A block copolymer with 5t (ends) was immobilized on this.

After thoroughly washing the gel column with PBS, PBS 370- containing 20mM of 2-mercaptoethanol as a reducing agent was passed through the column to remove the fixed block copolymer [PEG-P (
Asp)-terminal 5) IE was drained and lyophilized.

Dialysis (Spectrabore 7, molecular weight cutoff 1000.z distilled water), then gel filtration (Sephadex G-25PB)
Block copolymer obtained by removing low-molecular-weight compounds from S)?
199.8 mg of 2,2'-dipyridyl disulfide was added to 1140 ml of ethanol in 20 ml of ethanol, reacted for 2 hours at room temperature, purified by dialysis, gel filtration, and freeze-dried. Yield 31.9 mg (Yield 6%
).

The rate of introduction of PDPi into the ends of the floc copolymer was 48% as determined by the same method as above.

PEG-P (Asp) -PDP (4b) PEG-PIAsp by introducing hair dryer mysif (ADR)
(ADR)] - To stabilize PDP (6), 9.5 μ of adriamycin hydrochloride was dissolved in 9.5 d of DMF,
To this was added 1.3 equivalents of triethylamine. This adriamycin was used as a guest appearance on a flock copolymer (4b).
) 12.4■ was dissolved in 0.4% of distilled water and added thereto, 50% of 1-ethyl-3-(3-dimethylaminoprobyl)carbodiimide (EDC) was added and reacted at 0°C for 4 hours. Ta.

After the 0 reaction, 50-mL EDC was added and the reaction was carried out at room temperature for 19 hours.
4,5) for 3 hours (Spectrabore 7, molecular weight cutoff 1000) L, gel filtration with Sephadex G-25 (
0.0, IH sodium acetate buffer, pH 4.5).

The obtained PEG-P[Asp(ADR)]-PDP(6
) was determined from the absorption of 485n-.
Approximately 30 equivalent% based on the carboxy group of polyaspartic acid
Met.

Introduction of FDP groups into antibodies for coupling is carried out using human immunoglobulin G (IgG, manufactured by Sigma) 35.2
Dissolve g in PBS, remove aggregates through a 0.45 μm filter, remove low molecular impurities through a Sephadex G-25 column, and then add 5PDP (5) 20mM.
Add 146 μl of ethanol solution containing
After 0 minutes of reaction, gel filtration (Sephadex G-
25 in PBS) to obtain an IgG-FDP(8) fraction.

The amount of FDP group introduced was determined using the method described above.
It was 3.5 to 5.6 per molecule.

Block copolymer (7) (PEG-P[Asp(A
DR)]-terminal S old and IgG-FDP (8) to generate the desired PEG-P[Asp(ADR))
The reaction to obtain -IgG (9) was carried out in two ways: with and without ultrasonic irradiation.

(a) When ultrasonic irradiation is not performed, PEG-P[Asp(A
DR)]-PDP(6) to PBS 4.9aj! Add 250d of 100mM dithiothreitol aqueous solution and react for 20 minutes at room temperature to dissolve the 5S in the PDP chain.
- After reducing the bond and converting it into a block copolymer (7) with terminal -8H groups, gel filtration (Sephadex G-
25 in PBS) to remove low molecular weight substances. Ig in this solution
G-FDP (8) (5.6 PDP chains per molecule of IgG)
A solution of 9.3 µm (containing 10%) in PBS 9- was added, and the mixture was reacted at room temperature for 17 hours.

After the reaction, the reaction mixture was subjected to gel filtration (Sephacryl S-20
0, in PBS), and each fraction was subjected to high performance liquid chromatography (HPLC) C column: Asahi Back G5-520. Solvent: Q, 1M sodium phosphate buffer (pH 7, 5, 0, containing 3M NaCl)]
I divided it.

The gel filtration efflux curve is shown in FIG. 3, and the HPLC analysis chart is shown in FIG. 4.

The first peak flowing around 105d in FIG. 3 was assigned to the peak of the PEG-P[Asp(ADH)]-terminated SH(7) micelle that did not react with the antibody. 2nd figure in figure 3
As a result of HPLC analysis, the peak was found to be approximately the same as 1 gG, and it showed an absorption of <47 On- based on ADH. P [85p(ADH)]-1g
It was confirmed that it was G(9).

(b) When performing ultrasonic irradiation, a block copolymer (6
) was dissolved in PBS 5.25 affi, 250 m of a 100-dithiothreitol aqueous solution was added, and the reaction was carried out at room temperature for 20 minutes to reduce the 15S-bond in the PDP chain and form a block copolymer (7 ) and then gel filtration (Sephadex G-25, in PBS) to remove low molecular weight substances.

To this solution, add 12.6 μg of IgG-FDP (8) (containing 3.5' PDP chains per IgG molecule) to PBS 10
Dissolve it in d, add it, and irradiate it with ultrasonic waves (81 types: Valet
cell disrupter ModelUC[)
110) was repeatedly irradiated for 1 minute and allowed to stand for 1 minute, and the reaction was carried out at 15° C. for 2 hours.

After the reaction, the reaction mixture was subjected to gel filtration (Sephacryl S-30
0, in PBS) and for each fraction) IPL.
CC column: Asahi Back G5-520. Solvent: 0.1
M sodium phosphate buffer (pH 7, 5, 0, 3M Na
C1-containing)] for 9 minutes.

The gel filtration efflux curve is shown in FIG. 5, and the HPLC analysis chart is shown in FIG. 6.

The gel filtration efflux curve showed a peak with a shoulder on the left, and the portions before and after this were fractionated into five fractions (F1 to F5) and analyzed. From Fl to F3, the desired PEG-P [
Asp (ADR)] -1gG (9) flows out,
The block copolymer PEGP (ASP (ADH
)]-Terminal SR (7) was flowed out without forming micelles due to its low concentration.

In order to investigate the effect of ultrasonic irradiation on the reaction, each fraction obtained in (a) and 0) above was irradiated with 280 nm
The coupling efficiency and the composition of the obtained target product were investigated from the absorption of 485r+w+ (or 470 nm), and the results shown in Table 1 were obtained.

The cambling efficiency is expressed as the ratio (%) of ADR in the target compound (9) to the total H in the raw material (7), and the composition is ADR/IgG and PEG-P [Asp (ADR)
]/IgG.

As is clear from the results in Table 1, ultrasonic irradiation showed higher coupling efficiency. The reason is that the raw material PEG-P [Asp (ADR)] - terminal S)! This is thought to be because the micelle structure of (7) was destroyed, making the reaction with IgG more likely.

The obtained compound is the target PEG [Asp (AD
R) ] -IgG (9), under the same conditions as (b), PEG-P [Asp(ADR)] which does not have a group for coupling at the terminal and I
When mixed with gG and analyzed by HPLC, both components were separated with clear peaks, and PEG-P[Asp(ADR
)] flowed out as micelles, and absorption of <470n- was not observed in the component showing the IgG peak based on ADR. This [(PLC chart is shown in FIG. 7.

Test Example 1 (Reducing Agent Stability Test) The present compound PEG-P [Asp(
ADR) ] IgG (9) (ADR) 1.87 X
600 μl of a PBS solution containing 10-'M dithiothreitol was added to 600 μl of a PBS solution containing 10-'M, and the mixture was left at 28°C for 30 minutes.
r ModelUCD 100) was irradiated for 1 minute and allowed to stand for 1 minute, then reacted at 25°C for 35 minutes.
A reaction mixture of seeds was used as a sample, and gel filtration type) IPLc (
Column: Asahi Back G5-520. Solvent: 0. IM
Sodium phosphate buffer (pH 7, 5, 0, 3M N
aC1-containing)] for 9 minutes.

As a result, the sample that was simply left out had a peak that did not change from that of the untreated sample and leaked into (the same location as) the IgG outflow volume. This indicates that the disulfide bonds linking the ProTuc copolymer and the antibody were not reduced by dithiothreitol. On the other hand, in the sample irradiated with ultrasound, some disulfide bonds were broken and PEGP separated from the antibody:Asp(ADR)]-terminal S)
1 formed micelles and leaked out before IgG.

From the above, even in the presence of dithiothreitol, in which normal disulfide bonds are completely dissociated, the present compound PEG-P [Asp(8DR) ] -1gG
It was confirmed that the disulfide bond in (9) is very stable.

The gel filtration type HPLC chart used in this test is shown in FIG.

Test Example 2 (micelle stability test) ADR, PEG-P [85p (ADR)] and PEG-
Three types of compounds of P[Asp(ADR)]-TgG were used as samples, and the ADR concentration of each sample was 10-'~
Sample solutions (in isotonic phosphoric acid solution with pH 7.4) with various concentrations in the range of 10-'M were prepared, and the fluorescence caused by ADR (excitation: 471 nm, fluorescence 595 nm) was measured for each sample solution. As a result, the fluorescence intensity of the sample f4 solution containing PEG chains was significantly weaker than that of the ADR solution.

Next, sodium dodecyl sulfate (
After adding SOS) to a concentration of 1%, the fluorescence was measured in the same manner as above. The fluorescence intensity of all sample solutions increased significantly, but the intensity order was ADR>PEG-
PiAsp(ADR)]>PEG-P[Asp(AD
R) i-IgG, and the fluorescence intensity of the compound of the present invention was the weakest.

From the above, it can be seen that the compound of the present invention has an ADR of PE in solution.
ADR by forming micelles surrounded by G chains
It is thought that the fluorescence intensity caused by this has become weaker, and that the fluorescence intensity has increased due to the micelles being destroyed by the addition of the surfactant (SDS).

It was also found that the formation of micelles resulted in the stability of the disulfide bonds in Test Example 1.

〔Effect of the invention〕

ADVANTAGE OF THE INVENTION The present invention provides a novel target-directed macromolecular pharmaceutical compound that maintains a target-directed substance in a stable bond without decreasing its water solubility even when a large amount of drug is bound within the molecule, and its synthetic intermediates. It was done.

The target-directed polymeric pharmaceutical compound of the present invention has the excellent property of effectively delivering a large amount of drug to a desired site or component within a living body, and having almost no antigenicity. This is expected to make a significant contribution to the medical field in the future.

[Brief explanation of drawings]

Figure 1 is a structural schematic diagram of the target-directed polymeric pharmaceutical compound of the present invention, Figure 2 is the procedure for synthesizing the compound of the present invention, and Figure 3 is the coupling of the block copolymer and antibody during the synthesis of the compound of the present invention. Figure 4 is an HPLC chart for analyzing the flow-off fraction of Figure 3. Figure 5 is a gel filtration curve of the reaction mixture carried out without ultrasound. Efflux curves of gel filtration of the reaction mixture under sonic irradiation, Figure 6 is an HPLC chart for analyzing the effluent fraction of Figure 5, Figure 7 is the flow curve of the gel filtration of the reaction mixture carried out under sonic irradiation;
ADR)] Figure 8 is an HPLC chart for evaluating the stability of the compound of the present invention against reducing agents, Figure 9 is the fluorescence intensity and solution of the compound of the present invention based on adriamycin. Figures are shown in which the relationship between concentration and whether or not micelles are destroyed by surfactant (SOS) is compared with similar compounds.

Claims (1)

[Claims] 1. Sites other than the hydrophilic segment of a block (or graft) copolymer having a hydrophilic segment and a pharmacologically functional segment to which a drug is bound and a target-directing substance (i.e., a desired site or component in a living body) A target-directed polymeric pharmaceutical compound formed by bonding a substance that has high affinity for the target substance directly or via a linking chain. 2. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (I) (In the formula, l is 1 to 30, n is 5 to 400, m is 1 to 30
0, x represents an integer from 0 to 300, and R^1 represents m in the molecule.
The residues are the same or different and are selected from OH and drug residues, at least one of R^1 represents a drug residue, and R^2 represents a target-directing substance residue. ,R
^3 indicates CH_3, C_2H_5, etc., and A indicates a direct bond or a bond chain resulting from a coupling agent used in the bond reaction. ) The target-directed polymeric pharmaceutical compound according to claim 1. 3. The target-directed polymeric pharmaceutical compound according to claim 1 or 2, wherein the target-directed substance is an antibody. 4. Claims 1 to 4, wherein the drug is an anticancer drug.
3. The target-directed polymeric pharmaceutical compound according to 3. 5. The bonding chain A resulting from the coupling agent has the formula (II)-C
OCH_2CH_2SSCH_2CH_2CO-...
5. The target-directed polymeric pharmaceutical compound according to claim 2, which is a divalent chain compound residue represented by (II). 6. The target-directed polymeric pharmaceutical compound according to claims 2 to 5, wherein the bond between the target-directed substance residue R^2 and the binding chain A is an amide bond. 7. The target-directed polymeric pharmaceutical compound according to claims 4 to 6, wherein the anticancer agent is adriamycin. 8. An intermediate for synthesizing a target-directed polymeric pharmaceutical compound comprising a block (or graft) copolymer having a hydrophilic segment and a functional group-bearing segment capable of binding a drug and/or a target-directing substance. 9. General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (III) (In the formula, n is 5 to 400, m is 1 to 300, and x is zero or an integer of 1 to 300. , Y are the same or different and OH
and drug residues, Z is -COCH
The target-directed polymeric drug according to claim 8, characterized in that it consists of a block copolymer derivative represented by _2CH_2SH or ▲ where there is a numerical formula, chemical formula, table, etc., and R^3 represents CH_3, C_2H_5, etc.) Intermediate for compound synthesis.