JP2002060351A - Dds compound comprising drug having hydroxy group - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a drug delivery system(DDS) compound excellent in stability in blood serum and capable of making a pharmaceutical compound which is an active ingredient regioselectively migrate to a tumorous site, or the like. SOLUTION: This DDS compound is represented by the formula (I): A-W-N (R1)-C(R2)(R3)-O-Q (A denotes a polymer which is a drug carrier; W denotes a spacer containing one amino acid residue binding to the nitrogen atom in the formula at the C-terminal or a spacer containing an oligopeptide residue composed of 2-8 amino acid residues binding to the nitrogen atom at the C- terminal with a peptide bond; R1, R2 and R3 denote each hydrogen atom, an alkyl group, an aryl group, carboxy group or an alkoxycarbonyl group; any two of the R1, R2 and R3 may mutually be bound to form a 4- to an 8-membered ring; and O-Q denotes a residue of the pharmaceutical compound having hydroxy group).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a drug delivery system (DD) in which a drug carrier such as a polysaccharide derivative and a pharmaceutical compound such as an antitumor agent are bound via a spacer.
S) Compounds.

[0002]

2. Description of the Related Art Antitumor agents used in the treatment of solid cancers such as lung cancer and gastrointestinal cancer and blood cancers such as leukemia are administered systemically by an administration route such as intravenous administration or oral administration and then specified. To a tumor site to inhibit or suppress the growth of cancer cells, thereby exerting a therapeutic effect. However, systemically administered antitumor agents are rapidly taken up from the blood into the liver and reticuloendothelial organs, or are rapidly excreted in the urine. Migration may be restricted. In addition, because the selectivity of a normal antitumor agent itself to transfer to a tumor site (tumor selectivity) is low, the antitumor agent is widely distributed to various cells and tissues throughout the body, and is distributed to normal cells and tissues. On the other hand, it has a problem that it acts as a cytotoxin and causes an extremely high rate of side effects such as diarrhea, fever, vomiting, and hair loss. Therefore, there is a need for the development of means for efficiently and selectively transferring an antitumor agent to a tumor site.

As one of such means, a polysaccharide derivative is used as a drug carrier, and an antitumor agent is bound to the polysaccharide derivative to delay the disappearance of the antitumor agent in the blood, and at the same time, to a cancer tissue. A method for increasing directivity has been proposed. Compounds in which a drug is bound to the carboxyl group of a polysaccharide having a carboxyl group via a peptide chain (International Publication W
O094 / 19376), a product obtained by introducing a drug into a carboxymethylated mannoglucan derivative via a Schiff base or an amide bond (Japanese Patent Publication No. 7-84481),
The use of a polyalcoholated polysaccharide derivative as a drug carrier and binding of a drug via a peptide chain, and further via a peptide chain and a paraaminobenzyloxycarbonyl group (WO99 / 61061) and the like are disclosed. .

[0004] However, these means are mainly intended for binding a drug to a drug carrier or the like via an amino group of a pharmaceutical compound.
When the drug compound is bonded to the above carrier or the like via a hydroxyl group, the original site selectivity of the DDS compound may not be exhibited. That is, when the drug compound is bound to the drug carrier or the like via a hydroxyl group, the stability of the DDS compound in serum is extremely low, and the drug compound is released in the blood. A problem has arisen in that a rapid drug transfer is not achieved.

[0005]

An object of the present invention is to provide a DDS compound in which a pharmaceutical compound having a hydroxyl group such as an antitumor agent or an anti-inflammatory agent and a drug carrier are bound via a spacer containing 1 to 8 amino acids. The present invention provides a DDS compound which has excellent stability in serum and is capable of site-selectively transferring a pharmaceutical compound as an active ingredient to a tumor site or the like, and further has an antitumor agent having a hydroxyl group To reduce the side effects such as

[0006]

Means for Solving the Problems As a result of intensive efforts to solve the above-mentioned problems, the present inventors have found that a pharmaceutical compound having a hydroxyl group such as an antitumor agent or an anti-inflammatory agent and a drug carrier are 1-8.
DD connected via a spacer containing two amino acids
In the S compound, when a substituted or unsubstituted aminomethylene linker is further inserted between the spacer and the drug compound, the compound has excellent stability in serum, and can reliably and selectively select the drug compound for a tumor site or the like. It has been found that it is possible to provide a DDS compound that can be transferred to
Furthermore, it has been found that the DDS compound of the present invention reduces side effects such as diarrhea as compared with the case where the pharmaceutical compound is used alone. The present invention has been completed based on these findings.

That is, the present invention provides a compound represented by the following formula (I): AWN (R ¹ ) -C (R ² ) (R ³ ) -OQ (where A represents a polymer which is a drug carrier; Formula (I)
A spacer containing one amino acid residue bonded to the nitrogen atom at the C-terminus or an oligo composed of two to eight peptide-bonded amino acid residues bonded to the nitrogen atom at the C-terminus in formula (I) R represents a spacer containing a peptide residue;
¹ , R ² and R ³ each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, a carboxyl group or an alkoxycarbonyl group, and R ¹ , R ² , And R ³ may combine with each other to form a 4- to 8-membered ring;
Q represents the residue of a pharmaceutical compound having a hydroxyl group).

[0008] According to a preferred embodiment of the above invention, the drug carrier is a polysaccharide derivative having a carboxyl group.
The above-mentioned DDS compound, wherein W is a spacer containing an oligopeptide residue composed of 2 to 8 amino acid residues bonded with a peptide; the above-mentioned R ¹ , R ² , and R ³ are hydrogen atoms. DDS compound; the above-mentioned DDS compound, wherein the polysaccharide derivative having a carboxyl group is carboxy C _1-4 alkyl dextran polyalcohol;
A dextran polyalcohol as described above, wherein the dextran polyalcohol constituting the C _1-4 alkyldextran polyalcohol is a dextran polyalcohol obtained by treating dextran under substantially completely polyalcoholizable conditions; and Provided is a DDS compound as described above, wherein the _1-4 alkyl dextran polyalcohol is carboxymethyl dextran polyalcohol.

According to a further preferred embodiment, the above-mentioned DDS compound, wherein the pharmaceutical compound is an antitumor agent or an anti-inflammatory agent; the pharmaceutical compound is 1- [2-amino-6- (4-[(E) -3- [ The above DDS compound which is 4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinol; and W is -Gly -Gly-Phe-Gly-
The above DDS compound is provided.

From another point of view, the D represented by the above formula (I)
A medicament comprising a DS compound is provided by the present invention. This medicament can be used for treating a tumor or preventing and / or treating an inflammatory disease, depending on the type of the pharmaceutical compound. Further, the present invention provides a method for treating a tumor, comprising a step of administering a therapeutically effective amount of the DDS compound represented by the above formula (I) to a mammal including a human. Also provided is a method for preventing and / or treating an inflammatory disease, the method comprising a step of administering a preventive and / or therapeutic effective amount of the DDS compound represented by the above formula (I) to mammals including humans. Is done.

From another viewpoint, the following formula (II): PZN (R ¹ ) -C (R ² ) (R ³ ) -OQ (wherein P represents a hydrogen atom or an amino-protecting group; Z
Is composed of one amino acid residue linked at the C-terminus to the nitrogen atom in formula (II) or two to eight amino acids linked to the nitrogen atom at the C-terminus in formula (II). R ¹ , R ² , and R ³ each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, a carboxyl group, or an alkoxycarbonyl group; R ¹ , R ² ,
And any two of R ³ are bonded to each other to form 4 to 8
OQ represents a residue of a pharmaceutical compound having a hydroxyl group).

According to a preferred embodiment of the compound,
R ¹ , R ² and R ³ are hydrogen atoms, and the pharmaceutical compound is 1-
[2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl)-
1-piperazinyl] -1-propenyl] -1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinol, wherein Z is -G
There is provided a compound as described above which is ly-Gly-Phe-Gly-. formula
The compound represented by the formula (II) is a DDS represented by the formula (I).
It can be used for the production of compounds.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The DDS compound provided by the present invention is represented by the formula (I): AWN (R ¹ ) -C (R ² ) (R ³ ) -OQ.
In the formula, OQ represents a residue of a pharmaceutical compound having a hydroxyl group (O in the formula represents an oxygen atom constituting the hydroxyl group),
The residue of the pharmaceutical compound contained in the DDS compound of the present invention is:
For example, it refers to a main partial structure of a pharmaceutical compound used for treating and / or preventing diseases of mammals including humans as medicaments such as antitumor agents, anti-inflammatory agents, and antibacterial agents. However, the use of the pharmaceutical compound is not limited to those described above, and any pharmaceutical compound may be used as long as it has one or more hydroxyl groups. As used herein, the term “pharmaceutical compound” also includes a prodrug compound which contains the main structure of a compound which itself has a medicinal action as a partial structure and can regenerate the compound in vivo.

In the present specification, the residue of a pharmaceutical compound means a residue obtained by removing a hydrogen atom from one hydroxyl group of a pharmaceutical compound having one or more hydroxyl groups. That is, in the present specification, the pharmaceutical compound is HO-
Q (HO- in the formula represents one hydroxyl group of one or more hydroxyl groups of the pharmaceutical compound), and the residue of the pharmaceutical compound is represented by OQ.

The type of the pharmaceutical compound is not particularly limited,
For example, an antitumor agent or an anti-inflammatory drug is suitable. Examples of the antitumor agent include 5-fluorouridine such as 5′-deoxy-5-fluorouridine (doxofluridine) and 5′-deoxy-5-fluorocytidine, 5-fluorocytidine derivatives, and podophyllotoxins such as etoposide. Derivatives, camptothecin derivatives having a hydroxyl group such as 7-ethyl-9-hydroxycamptothecin, taxol or its derivatives, chartreusin
Or a derivative thereof, an ellipticin derivative having a hydroxyl group such as 9-hydroxy ellipticine, radicicol (radi
An anticancer macrolide having a phenolic hydroxyl group such as cicol) or oximidine I can be used. As the anti-inflammatory drug, for example, steroidal anti-inflammatory drugs such as hydrocortisone and prednisolone can be used.

In the formulas (I) and (II), R¹, R^Two,
And R^ThreeEach independently have a hydrogen atom and a substituent
Some alkyl groups, some aryls may have substituents
A carboxyl group or an alkoxycarbonyl group
You. R¹, R^Two, And R^ThreeAny two of them are connected
Together, they may form a 4- to 8-membered ring. R¹, R^Two,as well as
R ^ThreeThe alkyl group represented by is linear, branched, cyclic, or
May be any combination thereof, for example, carbon
Number 1 to 10, preferably 1 to 6 carbon atoms, more preferably
Can be an alkyl group having 1 to 4 carbon atoms.
Examples of the alkyl group include a methyl group, an ethyl group,
Propyl group, isopropyl group, cyclopropyl group, n-butyl
Group, sec-butyl group, tert-butyl group, isobutyl group,
Cyclobutyl group, cyclopropylmethyl group, n-pentyl
And n-hexyl group. R¹,
R^Two, And R^ThreeAny two of them are combined with each other to form 4
May form an 8-membered ring, and one or two or more rings may be formed on the ring.
May be substituted. R¹And R^TwoIs combined
To form a ring, and R^TwoAnd R^ThreeBinds to form a ring
The following examples are given as examples of the formation.
be able to.

[0017]

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When the alkyl group has a substituent, the type of the substituent, the number of the substituents and the position of the substituents are not particularly limited, and when two or more substituents are present, they are the same or different. May be. Examples of the substituent that can be present on the alkyl group include, for example, a hydroxyl group, a halogen atom (which may be any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an alkoxyl group (a methoxy group,
Ethoxy group, n-propoxy group, etc.), substituted or unsubstituted aryloxy group (phenoxy group, etc.), amino group, monoalkylamino group (methylamino group, ethylamino group, etc.), dialkylamino group (dimethylamino group, Diethylamino group, ethylmethylamino group),
Examples include a mercapto group, an alkylthio group (such as a methylthio group and an ethylthio group), an amidino group, a guanidino group, a ureido group, a carboxyl group, an alkoxycarbonyl group, and an aryl group (such as a substituted or unsubstituted phenyl group).

When the aryl group represented by R ¹ , R ² and R ³ has a substituent, the type of the substituent, the number and the position of the substituent are not particularly limited, and two or more substituents are present. If so, they may be the same or different. As the substituent, the substituents exemplified for the above alkyl group can be used.

In the above substituents exemplified for the alkyl group, when the aryl ring has a substituent, the type of the substituent and the number and position of the substituent are not particularly limited, and two or more substituents may be used. When they are present, they may be the same or different. Examples of the substituent on the aryl ring include an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxyl group (such as a methoxy group and an ethoxy group), an alkenyl group (such as a vinyl group and an allyl group), and an alkynyl group (such as a propargyl group). ), A hydroxyl group, a halogen atom (which may be any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a carboxyl group, an alkoxycarbonyl group (such as a methoxycarbonyl group), an alkanoyl group (such as an acetyl group), and a haloalkanoyl group (Such as a trifluoroacetyl group), an aryl group (such as a phenyl group or a naphthyl group), an aralkyl group (such as a benzyl group), an aryloxy group (such as a phenoxy group), an aralkyloxy group (such as a benzyloxy group),
An aroyl group (such as a benzoyl group), a heteroaryl group (such as a pyridyl group or a quinolyl group), an amino group, a monoalkylamino group, a dialkylamino group, a carbamoyl group,
Examples include, but are not limited to, nitro, cyano, amidino, guanidino, ureido, alkylsulfinyl, alkylsulfonyl, thiol, and alkylthio groups.

As the spacer represented by W, a spacer containing one amino acid residue or peptide-bonded 2
And a spacer containing an oligopeptide residue composed of from 8 to 8 amino acid residues. The spacer may be a residue of one amino acid (meaning a residue obtained by removing one hydrogen atom and one hydroxyl group from an amino group and a carboxyl group of an amino acid, respectively), or two to eight peptide-bonded residues. It has the form of a residue of an oligopeptide containing an amino acid residue (residue obtained by removing one hydrogen atom and one hydroxyl group from the N-terminal amino group and the C-terminal carboxyl group, respectively) At the C-terminus (carboxyl group in the case of a spacer containing one amino acid)
It is arranged so as to be peptide-bonded to the nitrogen atom of the group represented by -N (R ¹ ) -C (R ² ) (R ³ ) -OQ.

Generally, the bond between the drug carrier represented by A and the spacer is formed by a peptide between the carboxyl group of the drug carrier and the N-terminus of the spacer (an amino group in the case of a spacer containing one amino acid). It is formed by bonding. However, the bond between the spacer and the drug carrier is not limited to the peptide bond described above, but may be another chemical bond or a bond using one or more spacers. For example, when the spacer includes one or two or more residues of a dicarboxylic acid compound (for example, a residue of a dicarboxylic acid such as succinic acid) as a constituent unit, and the both ends are carboxyl groups. For example, a reactive amino group in a drug carrier can be used for binding.

Preferred spacers are those containing oligopeptide residues composed of 2 to 6 amino acid residues. The type of amino acid constituting the spacer is not particularly limited, for example, L- or D-amino acid, preferably
L-amino acids can be used, in addition to α-amino acids,
β-alanine, ε-aminocaproic acid, γ-aminobutyric acid, and the like may be used. It is preferable that such an amino acid other than the α-amino acid is arranged at a position close to the drug carrier in the spacer.

The amino acid sequence in the case of using a spacer containing an oligopeptide residue is not particularly limited. For example, the amino acid sequence of a dipeptide residue (S
Indicates a residue of a hydrophobic amino acid, T indicates a residue of a hydrophilic amino acid, and -ST- indicates that the hydrophobic amino acid (S) and the hydrophilic amino acid (T) are N-terminal and C-terminal, respectively. N-terminal amino group and C
Which means a residue obtained by removing one hydrogen atom and one hydroxyl group from the terminal carboxyl group), or a spacer containing the residue of the dipeptide as a partial peptide sequence. As the hydrophobic amino acid, for example, phenylalanine, tyrosine, leucine and the like can be used, and as the hydrophilic amino acid,
For example, glycine, alanine and the like can be used. The spacer may have a repeating sequence of such dipeptide residues (eg, -STST-, -STSTST-, etc.).

When a spacer containing such a dipeptide structure is used, the spacer is hydrolyzed at a tumor site or an inflammatory site considered to be rich in peptidase, and a high concentration of a pharmaceutical compound is released in a short time at the site. The partial structure formed by bonding the above-mentioned spacer containing the dipeptide and the pharmaceutical compound is a preferable partial structure of the DDS compound of the present invention. As a residue of a pharmaceutical compound,
When using the residue of an antitumor agent which exhibits a concentration-dependent antitumor effect (an antitumor agent which exhibits a stronger antitumor effect at a higher concentration: a concentration-dependent antitumor agent such as doxorubicin) It is preferable to use a spacer consisting of the above dipeptide residue represented by -XZ- or a spacer containing the dipeptide residue as a partial peptide sequence.

On the other hand, even when an antitumor agent (for example, methotrexate) which requires a prolonged action time at a certain concentration or more is used as a residue of a pharmaceutical compound, a high antitumor effect can be obtained by using the above spacer. In some cases, the effect can be achieved, but in general, it is necessary to select a preferable spacer from the viewpoint of the pharmacokinetic characteristics and toxicity of the antitumor agent without being limited to the above-mentioned spacer. In general, it is preferable to select the above-mentioned spacer capable of releasing a high-concentration pharmaceutical compound in a short time for a cancer type that grows rapidly. In particular, the rate of release of the pharmaceutical compound in the DDS compound of the present invention is determined by selecting an appropriate spacer from the viewpoint of the rate of enzymatic degradation since the enzymatic degradation of the spacer portion is at a substantially rate-determining step. Can easily be achieved.

Specific examples of oligopeptide residues that can be used as a spacer are shown in the following table. However, the spacer used in the DDS compound of the present invention is not limited to the following. It goes without saying that a person skilled in the art can appropriately make an optimal release rate of the pharmaceutical compound (in the table, the peptide sequence is N-terminal on the left side and -N (R ¹ ) -C The nitrogen atom of the group represented by (R ² ) (R ³ ) -OQ forms a peptide bond, D-Phe represents a D-phenylalanine residue, and the other amino acids represent L-amino acids. The magnitude was determined by the degree of the effect of doxorubicin-bound DDS compound on Walker 256 tumor-bearing rats or the concentration of free doxorubicin in the tumor site of Walker 256 tumor-bearing rats.) For example, for doxorubicin, (N-terminal)-
It is preferable to use a spacer such as Gly-Gly-Phe-Gly- which can release a high concentration of a pharmaceutical compound in a short time.

[0028]

[Table 1]

As the Z in the compound represented by the formula (II), the amino acid residue or oligopeptide residue described for the spacer represented by W can be used. P represents a hydrogen atom or a protecting group for an amino acid. The type of amino-protecting group is not particularly limited, for example,
Protective Groups in Organic Synthesi
s), TW Greene, John Wiley and Sons, Inc. (John Wiley)
& Sons Inc.) (1981) can be suitably used.

As the drug carrier represented by A, not only polysaccharide derivatives but also synthetic polymers can be used. As the polysaccharide derivative and the synthetic polymer, any one may be used as long as it does not substantially exhibit toxicity to the living body and can act as a drug carrier. For example, any of the polysaccharide derivatives and synthetic polymers conventionally used for the production of DDS compounds can be used for the DDS compound of the present invention.
For example, a polysaccharide derivative having a carboxyl group can be suitably used for the DDS compound of the present invention, and a polyalcoholized polysaccharide derivative is particularly preferable. Also, as a synthetic polymer,
Examples thereof include polyethylene glycols; polyamino acids such as polyglutamic acid, polyaspartic acid, and polylysine; and derivatives of polyvinyl compounds such as N- (2-hydroxypropyl) methacrylamide derivatives.

For example, polysaccharides such as dextran and inulin, polysaccharide derivatives into which a carboxylalkyl group is introduced such as carboxymethyl dextran and carboxymethyl mannoglucan, carboxy disclosed in WO97 / 46260
_{Carboxyalkylated} derivatives of polyalcohols derived from polysaccharides such as C1-4 alkyl dextran polyalcohol derivatives, copolymerization of N- (2-hydroxypropyl) methacrylamide and acrylic acid copolymers (HPMA) Polymers, synthetic poly (amino acids) such as poly (L-lysine), poly (L-aspartic acid), proteins such as human serum albumin, polyethers having a hydroxyl group at a terminal such as polyethylene glycol, etc. can be used. It is not limited to these.

More specifically, the polysaccharide derivative having a carboxyl group is, for example, any polysaccharide or a derivative obtained by chemically or biologically modifying them and having a carboxyl group in the molecule. A thing may be used. For example, besides polysaccharides such as hyaluronic acid, pectic acid, alginic acid, chondroitin, heparin, pullulan, dextran, mannan, chitin, inulin, levan, xylan, araban, mannoglucan,
Polysaccharides such as chitosan and pullulan in which a functional group having a carboxyl group has been introduced into some or all of the hydroxyl groups can be used.

For example, those obtained by alkylating a hydroxyl group with carboxy C _1-4 or those obtained by esterifying a hydroxyl group with one carboxyl group of a polybasic acid can be suitably used. In addition, a product obtained by introducing a functional group having a carboxyl group after polyalcoholizing the above polysaccharide may be used. As used herein, the term "polysaccharide derivative" includes a polysaccharide compound containing a saccharide as a constituent, and a compound obtained by partially or completely opening a cyclic sugar portion of the polysaccharide compound (eg, a polyalcohol compound).
It is necessary to interpret in the broadest sense, including Among these polysaccharide derivatives, it is preferable to use carboxy C _1-4 alkyl dextran polyalcohol, carboxy C _1-4 alkyl pullulan polyalcohol and the like. Hereinafter, the case where carboxy C _1-4 alkyl dextran polyalcohol is used for the production of the DDS compound of the present invention will be described more specifically, but the drug carrier in the DDS compound of the present invention is carboxy C _1-4 alkyl dextran polyalcohol. It is not limited to.

The polyalcohol degree of carboxy C _1-4 alkyl dextran polyalcohol used in the manufacture of a medicament carrier of the present invention is not particularly limited, dextran polyalcohol constituting the carboxy C _1-4 alkyl dextran polyalcohol is substantially It is preferably dextran polyalcohol obtained by treating dextran under conditions which can be completely polyalcoholized.

The type of dextran used for producing the carboxy C _1-4 alkyl dextran polyalcohol is not particularly limited, and may contain an α-D-1,6- bond in an arbitrary ratio. For example, dextran having an α-D-1,6-bond ratio of 85% or more, 90% or more, or 95% or more can be used. Although the molecular weight of dextran is not particularly limited, for example, dextran having a molecular weight of about 10,000 to 2,000,000, preferably about 50,000 to 800,000 can be used. The C _1-4 alkyl which constitutes the carboxy C _1-4 alkyl dextran polyalcohol carboxy C _1-4 alkyl group, straight or branched C _1-4 alkyl chain, for example, methyl, ethyl , N-propyl group,
An isopropyl group, an n-butyl group, a sec-butyl group and the like can be used, but a methyl group can be preferably used.

When dextran is used as a starting material, a large excess of sodium periodate and sodium borohydride are successively allowed to act on dextran to produce dextran polyalcohol in which dextran is substantially completely polyalcoholized. be able to. However, the method of polyalcoholization of dextran is not limited to the above, and any method may be adopted as long as it can be used by those skilled in the art. Carboxy C _1-4 alkylation is, for example, chloroacetic acid, bromoacetic acid, α-chloropropionic acid, α-methyl-α-chloropropionic acid, β-chloropropionic acid, α-methyl for the hydroxyl group of dextran polyalcohol. -Β-chloropropionic acid, α-chlorobutyric acid, β-chlorobutyric acid, halogenated C _1-4 alkyl carboxylic acids such as γ-chlorobutyric acid, preferably chloroacetic acid to react the hydroxyl groups partially or completely with carboxy C It can be carried out by _1-4 alkylation.

For example, dextran polyalcohol is dissolved in an inert solvent not involved in the reaction (eg, water, N, N-dimethylformamide, dimethyl sulfoxide, etc.), and a base (eg, sodium hydroxide, potassium hydroxide, etc.) is dissolved. A halogenated C _1-4 alkylcarboxylic acid or a salt thereof may be added in the presence thereof, and the reaction may be carried out at a temperature in a range of from ice-cooling to about 100 ° C. for several minutes to several days. The degree of introduction of the carboxy C _1-4 alkyl group can be easily determined, for example, by appropriately selecting the reaction temperature of the carboxy C _1-4 alkylation and the amounts of the halogenated C _1-4 alkyl carboxylic acid and the base used as the reagent. Adjustable, such means are well known to those skilled in the art. The degree of carboxy C _1-4 alkylation to the hydroxyl group of dextran polyalcohol is not particularly limited,
For example, it is in the range of 0.01 to 2.0, preferably 0.1 to 1.0 per constituent sugar residue. In this way, an aqueous solution in the form of an alkali metal salt such as the sodium or potassium salt of carboxy C _1-4 alkyl dextran polyalcohol can be prepared.

In addition to the polysaccharide derivative in the form of an alkali metal salt prepared as described above, a polysaccharide derivative in the form of a salt of an organic amine may be used as a raw material for a drug carrier. Since the polysaccharide derivative in the form of a salt of an organic amine can be dissolved at a high concentration in a substantially water-free organic solvent, the use of this salt allows the reaction to be carried out in a non-aqueous system, thereby significantly increasing the reaction efficiency. May be able to. Examples of organic amine salts include, for example, salts of aliphatic amines such as triethylamine, trimethylamine, and triethanolamine.
N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, salts of alicyclic or aromatic amines such as dimethylaminopyridine, tetramethylammonium chloride, quaternary ammonium salts such as tetraethylammonium chloride and the like may be used. it can.

The conversion of the sodium salt of the polysaccharide derivative into the salt of an organic amine can be carried out using an ion exchange resin or the like. For example, the sodium salt of carboxymethyl dextran polyalcohol is dissolved in water and Bio-Rad AG50
After applying to a column packed with W-X2 (200-400 mesh, H ⁺ type) resin and eluting with water, an organic amine such as triethylamine can be added and freeze-dried. Also,
It is also possible to carry out the conversion in one step by dissolving the sodium salt of carboxymethyl dextran polyalcohol in water and passing it through a triethylammonium type resin.

The DDS compound represented by the formula (I) of the present invention can be produced, for example, according to the following scheme. After removing the protecting group at the N-terminus of the amino acid residue or oligopeptide residue represented by the formula (III) by an appropriate deprotection reaction to obtain the compound of the formula (III-A), the carboxyl group of the drug carrier is obtained. Can be produced by a method of bonding via an acid amide bond. For the formation of the acid amide bond, a conventional dehydration condensing agent used for peptide chain synthesis, for example, N, N'-
N, N'-dicycloalkylcarbodiimides such as dicyclohexylcarbodiimide (DCC), carbodiimide derivatives such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAPC), 1-hydroxybenzotriazole (HOB
In addition to benzotriazole derivatives such as T), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (E
EDQ) can be used. Further, the reaction may be performed by an active ester method, an acid halide method, or the like.

[0041]

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When the reaction using the polysaccharide derivative is carried out in a non-aqueous system, the reaction is carried out using an organic solvent substantially free of water and containing a reactive species (a salt of an organic amine of the polysaccharide derivative and a free or salt form of formula ( Any compound capable of dissolving the compound (III-A)) may be used. For example, it is preferable to use N, N-dimethylformamide, dimethylsulfoxide, acetamide, N-methylpyrrolidone, sulfolane and the like. The amount of the drug compound residue introduced into the drug carrier is not particularly limited, but should be appropriately selected from the viewpoints of the type of the drug compound residue, the pharmacokinetics, efficacy, toxicity, and the like of the DDS compound. Generally, a range of about 0.1 to 30% by weight, preferably about 2 to 15% by weight can be selected. The ratio of the drug compound residue introduced into the drug carrier can be easily determined by, for example, absorbance analysis.

The compound represented by the above formula (III) can be produced, for example, by the method shown in the following scheme. The compound represented by the formula (IV) (wherein L represents an acetoxy group or a hydroxyl group) and a pharmaceutical compound having a hydroxyl group are subjected to a substitution reaction under a basic condition or an acid catalyzed condition to obtain a compound represented by the formula: The compound represented by (IV-A) can be obtained. The compound represented by the formula (III) by deprotecting the protecting group for the N-terminal amino group of the compound represented by the formula (IV-A) under appropriate conditions, and then elongating the peptide chain as necessary. Can be obtained. The compound represented by the formula (IV) can be obtained, for example, by treating an oligopeptide having a protected N-terminal amino group with lead tetraacetate in a suitable solvent (AP Gledhill et. Al., J. . Org. Chem., 51, 3
196-3201, 1986). Alternatively, it can be obtained by treating an acid amide of an oligopeptide having a protected terminal amino group or an acid amide of an amino acid having a protected amino group with an aldehyde or ketone.

[0044]

Embedded image (In the scheme, Y represents an oligopeptide consisting of 1 to 8 amino acids in which the amino group is protected.)

The compound (IV-A) is obtained by subjecting a compound represented by the formula (IV) to a substitution reaction with a synthetic intermediate X-OH of a pharmaceutical compound having a hydroxyl group as shown in the following scheme. The formula (I
After the compound represented by VC), it can also be produced via an appropriate conversion reaction.

[0046]

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The working examples of the method for producing the DDS compound of the present invention are shown in the working examples. Those skilled in the art can appropriately select starting materials and reaction reagents based on the above general description and the specific description of the examples, and can appropriately modify or alter reaction conditions and steps as necessary. By adding, the DD of the present invention included in the above general formula (I)
S compounds and compounds encompassed by formula (II) can be prepared.

The DDS compound of the present invention has a desired pharmaceutical activity depending on the type of the residue of the pharmaceutical compound (for example, the residue of the pharmaceutical compound such as an antitumor agent or an anti-inflammatory agent). Is characterized in that it can be specifically expressed locally at the same time, and the toxicity of the pharmaceutical compound itself can be reduced. In particular, the DDS compounds of the present invention
It is useful for improving the site selectivity of a pharmaceutical compound having a hydroxyl group and reducing side effects associated therewith. When a pharmaceutical compound having a hydroxyl group is bound via an aminomethylene linker,
The DDS compound has excellent stability in serum and remarkably reduces release of a pharmaceutical compound in blood. As a result, selective release of the pharmaceutical compound at a local site such as a tumor site or an inflammatory site can be realized, and side effects can be reduced while maintaining the efficacy of the pharmaceutical compound. Side effects that are reduced include diarrhea, vomiting,
Fever, hair loss, and the like. Among them, a remarkable effect was also observed in terms of suppressing acutely occurring diarrhea.

The medicament containing the DDS compound of the present invention can be usually filled in a vial or the like in the form of a lyophilized product and used as a parenteral administration preparation such as an injection or infusion preparation which is dissolved when used. Although provided to the clinic, the pharmaceutical form of such a drug is not limited to the above embodiment. In the production of the above-mentioned preparations, for example, additives for preparations which can be used in the art, such as solubilizers, pH adjusters, and stabilizers, can be used. The dose of the DDS compound of the present invention is not particularly limited, but usually, the dose of the drug compound constituting the drug compound residue, the amount of the drug compound residue introduced into the DDS compound, the condition and disease of the patient Should be determined in consideration of the type of the product. For example, 1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] which is an antitumor agent as a pharmaceutical compound -1H-pyrazole-1-
Yl) -4-pyrimidinyl] -3-azetidinol
When administering a DDS compound introduced at a rate of about% by weight, in the case of parenteral administration are generally day per body surface area 1 m ² per about 0.1 to 100 mg approximately, preferably about 1 to 30 mg It is preferable to administer once within the range described above and repeat every 3 to 4 weeks.

[0050]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. In the following examples, Boc: tert-butoxycarbonyl group, AM: aminomethylene linker, Dex: dextran, PA: polyalcohol, Fmoc: 9-fluorenylmethoxycarbonyl group, and drug (1) represents 1- [ 2-amino-6-
(4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinol Represent.

Example 1 tert-butyl 2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl] oxy) methyl] amino] -2-oxoethyl carbamate {Boc-Gly-AM-drug (1)} Example 1-1 ([[2-[(tert-butoxycarbonyl) amino] acetyl] amino) methyl acetate Boc -Glycylglycine (hereinafter referred to as "Boc-Gly-Gly-OH" in the Examples and the same applies to similar substances) to a mixture consisting of 4.64 g, 120 ml of tetrahydrofuran (THF) and 40 ml of toluene. 1.62 ml of pyridine and 9.75 g of lead tetraacetate / Pb (OAc) ₄ were added, and the mixture was heated under reflux for 4 hours. After the reaction solution was cooled to room temperature, insolubles were removed by filtration through Celite, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and then with saturated saline, and then the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, developing with a mixed solvent of ethyl acetate-hexane (1: 1) and concentrating the fraction containing the desired compound to give 2.80 of the title compound. g was obtained as a colorless syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (s, 9 H), 2.07 (s,
3 H), 3.83 (d, 2 H, J = 5.6 Hz), 5.1-5.2 (m, 1
H), 5.26 (d, 2 H, J = 7.3 Hz), 7.25-7.35 (m, 1 H).

Example 1-2 tert-butyl 2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl] oxy) methyl] amino] -2-oxoethyl carbamate {Boc-Gly-AM-drug (1)} 1- [2-amino-6- (4-[(E) -3- [4- (3 , 5-Difluorophenyl) -1-piperazinyl] -1-propenyl] -1H-pyrazole-1-
Yl) -4-pyrimidinyl] -3-azetidinol ｛drug (1)｝ 4
After cooling a suspension of 8 mg of THF in 5 ml to 0 ° C., a 1M solution of sodium hexamethyldisilazide (NaHMDS) in 0.1M THF was added.
After stirring for 10 minutes, the compound 30 obtained in Example 1-1 was added.
A solution of mg in 2 ml of THF was added. After the reaction solution was stirred at 0 ° C. for 45 minutes, it was further stirred at room temperature for 1 hour. After water was added to the reaction solution, the mixture was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to preparative TLC and developed with a mixed solvent of methanol and chloroform (5:95) to give 28 mg of the title compound from the fraction containing the desired product. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (s, 9 H), 2.64 (t, 4 H, J
= 5 Hz), 2.65 (s, 3 H), 3.19 (d, 2 H, J = 7 Hz),
3.23 (t, 4 H, J = 5 Hz), 3.83 (d, 2 H, J = 6 Hz),
3.90-4.00 (m, 2 H), 4.20-4.30 (m, 2 H), 4.55-4.60
(m, 1 H), 4.78 (d, 2 H, J = 7 Hz), 4.82 (s, 2 H),
5.15-5.25 (m, 1 H), 6.03 (dt, 1 H, J = 16 Hz, 7 H
z), 6.11 (s, 1 H), 6.25 (tt, 1 H, J = 9 Hz, 2 Hz),
6.37 (dd, 2H, J = 11 Hz, 2 Hz), 6.38 (d, 1 H, J =
16 Hz), 6.98 (t, 1 H, J = 7 Hz), 7.74 (s, 1 H).

Example 1-3 (separate synthesis method) tert-butyl 2-([[((1-benzhydryl-3-azetidinyl))
Oxy] methyl] amino) -2-oxyethyl carbamate 1-benzhydryl-3-azetidinol 2.72 g and Example 1-
2.80 g of the compound obtained in 1 was dissolved in 28 ml of THF, 2.9 ml of a 4N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 4 hours. After adding 50 ml of water to the reaction solution and stirring for 1 hour,
Saturated saline was added, and the mixture was extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, developed with a hexane: ethyl acetate (2: 3) mixed solvent, and the fraction containing the target compound was collected. Concentration gave 1.11 g of the title compound as a colorless syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (s, 9 H), 2.90-2.95 (m, 2
H), 3.45-3.50 (m, 2 H), 3.76 (d, 2 H, J = 6 Hz), 4.
26 (m, 1 H), 4.33 (s, 1 H), 4.69 (d, 2 H, J = 7 H
z), 5.00-5.15 (br, 1 H), 6.70-6.85 (m, 1 H), 7.10-
7.50 (m, 10 H).

Example 1-4 (separate synthesis method) tert-butyl 2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl] oxy) methyl] amino] -2-oxoethyl carbamate {Boc-Gly-AM-drug (1)} 790 mg of the compound obtained in Example 1-3 was dissolved in 25 ml of ethanol, and then 10% palladium- 500 mg of carbon (containing 50% water) was added, and catalytic hydrogenation was performed under pressure (5 kg / cm ² ) for 20 hours. After insolubles were removed by filtration and the filtrate was concentrated, the residue was dissolved in chloroform and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was dissolved in 40 ml of dimethylformamide, and 4-chloro-6- (4-[(E) -3- [4
After addition of 603 mg of-(3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl-1H-pyrazol-1-yl) -2-pyrimidinylamine and 0.177 ml of triethylamine, 80 ° C. For 24 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of methanol: chloroform (2:98 to 4:96), and extracted with a solvent containing the target compound. By concentrating the residue, 729 mg of the title compound was obtained as a pale yellow amorphous. NMR
The spectrum was consistent with the compound synthesized in Example 1-2.

Example 2 2-amino-N-[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]- 1-propenyl] -1H-
Pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl]
[Oxy) methyl] acetamide {H-Gly-AM-drug (1)} 28 mg of the compound obtained in Example 1-2 was dried in 3 ml of dichloromethane.
After cooling to 0 ° C., 0.3 ml of trifluoroacetic acid (hereinafter abbreviated as TFA) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with a 1N aqueous sodium hydroxide solution. After the aqueous layer was extracted with chloroform, the organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was subjected to preparative TLC and developed with a water-methanol-chloroform (7: 3: 1) partition organic layer to obtain 12 mg of the title compound from the fraction containing the desired product. ¹ H-NMR (CDCl ₃ ) δ: 2.6-2.70 (m, 4 H), 2.63 (s, 3
H), 3.18 (d, 2 H, J = 7 Hz), 3.22 (t, 4 H, J = 5 H
z), 3.45 (brs, 2 H), 3.90-4.00 (m, 2 H), 4.20-4.30
(m, 2 H), 4.55-4.65 (m, 1 H), 4.79 (d, 2 H, J = 7
Hz), 4.83 (brs, 2H), 6.02 (dt, 1 H, J = 16 Hz, 7 H
z), 6.09 (s, 1 H), 6.24 (tt, 1 H, J = 9 Hz, 2 Hz),
6.35 (dd, 2 H, J = 11 Hz, 2 Hz), 6.36 (d, 1 H, J =
16 Hz), 7.72 (s, 1 H), 8.11 (brs, 1 H).

Example 3 tert-butyl 13-([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1- Propenyl] -5-
Methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy)-7-benzyl-2,5,8,11-tetraoxo-3,6,9,12-tetraazatri-1-decyl Carbamate B
oc-Gly-Gly-Phe-Gly-AM-drug (1)｝ 12 mg of dimethylformamide (hereinafter DM) of the compound obtained in Example 2
F2 ml) solution, 33 mg of Boc-Gly-Gly-Phe-OH, 10 mg of N-hydroxysuccinimide, and 18 mg of dicyclohexylcarbodiimide were added at 0 ° C, and the mixture was stirred at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with a 1N aqueous sodium hydroxide solution. After the aqueous layer was extracted with chloroform, the organic layers were combined and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to preparative TLC, and methanol-
The mixture was developed with a mixed solvent of chloroform (1: 9) to obtain 16 mg of the title compound from the fraction containing the target compound. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (s, 9 H), 2.60-2.70 (m, 4
H), 2.62 (s, 3 H), 3.05 (dd, 1 H, J = 14 Hz, 8 H
z), 3.18 (d, 2 H, J = 7 Hz), 3.22 (t, 4 H, J = 5 H
z), 3.7-4.0 (m, 9 H), 4.15-4.25 (m, 2 H), 4.50-4.5
5 (m, 1 H), 4.59 (dd, 1 H, J = 14 Hz, 7 Hz), 4.70
(dd, 1 H, J = 11 Hz, 6 Hz), 4.81 (dd, 1H, J = 11 H
z, 7 Hz), 4.99 (s, 2 H), 5.65-5.75 (m, 1 H), 6.02
(dt, 1 H, J = 16 Hz, 7 Hz), 6.07 (s, 1 H), 6.25 (t
t, 1 H, J = 9 Hz, 2 Hz), 6.36 (dd, 2 H, J = 11 Hz,
2 Hz), 6.37 (d, 1 H, J = 16 Hz), 7.15-7.30 (m, 5
H), 7.35-7.50 (m, 2 H), 7.55-7.65 (m, 1 H), 7.65-
7.70 (m, 1 H), 7.70 (s, 1 H).

Example 4 9H-fluoren-9-ylmethyl 2-[(2-[[([1- [2-amino-6
-(4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl-1H-pyrazol-1-yl)
-4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] -2-oxyethyl) amino] -1-benzyl-2-oxoethylcarbamate {Fmoc-Phe-Gly-AM-drug (1)} Example 1 65 mg of the compound obtained in 2, N-[(9H-fluoren-9-ylmethoxy) carbonyl] phenylalanine (Fmoc-Phe-O
H), 72 mg, and N-hydroxysuccinimide 22
To a solution of 5 mg of DMF was added 110 mg of DCC under ice cooling, and the mixture was stirred for 24 hours while gradually returning to room temperature. After diluting the reaction solution with ethyl acetate, a saturated aqueous solution of sodium hydrogen carbonate, water,
After washing with saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of methanol and chloroform (1: 9), and the fraction containing the desired product was concentrated to obtain 119 mg of the title compound. ¹ H NMR (CDCl ₃ ) δ: 2.5-2.6 (m, 4 H), 2.64 (s, 3
H), 3.0-3.1 (m, 1 H), 3.18 (d, 2 H, J = 7.8 Hz),
3.2-3.3 (m, 5 H), 3.8-3.9 (m, 1 H), 4.1-4.2 (m, 5
H), 4.3-4.4 (m, 2 H), 4.4-4.5 (m, 2 H), 4.6-4.7
(m, 2 H), 4.7-4.8 (m, 1 H), 6.03 (dt, 1 H, J = 15.
9, 6.6 Hz), 6.09 (s, 1 H), 6.25 (t, 1 H, J = 8.3 H
z), 6.36 (d, 2 H, J = 8.3 Hz), 6.38 (d, 1 H, J = 1
5.9 Hz), 7.1-7.3 (m, 7 H), 7.36 (t, 2 H, J = 7.3 H
z), 7.48 (d, 2 H, J = 7.3 Hz), 7.71 (s, 1 H), 7.72
(d, 2 H, J = 7.3 Hz), 8.01 (s, 1 H).

Example 5 2-amino-N- (2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl] oxy) methyl] amino] -2-oxoethyl)
3-Phenylpropanamide {H-Phe-Gly-AM-drug (1)} Compound obtained in Example 4 119 mg of 1,4-dioxane (4.0 ml)
400 l of piperidine was added to the solution, and the mixture was stirred for 2 hours. The reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography to give methanol: chloroform (1: 1).
9) The mixture was developed with a mixed solvent, and the fraction containing the desired product was concentrated to obtain 63 mg of the title compound. ¹ H NMR (CDCl ₃ ) δ: 2.5-2.6 (m, 4 H), 2.65 (s, 3
H), 2.81 (dd, 1 H, J = 13.6, 9.0 Hz), 3.18 (d, 2
H, J = 6.8 Hz), 3.2-3.3 (m, 5 H), 3.72 (dd, 1 H, J
= 9.0, 4.4 Hz), 3.9-4.0 (m, 4 H), 4.2-4.3 (m, 2
H), 4.5-4.6 (m, 1 H), 4.7-4.8 (m, 3 H), 6.05 (dt,
1 H, J = 15.9, 6.6 Hz), 6.11 (s, 1 H), 6.25 (t, 1
H, J = 8.3 Hz), 6.36 (d, 2 H, J = 8.3 Hz), 6.38
(d, 1 H, J = 15.9 Hz), 6.9-7.0 (m, 1 H), 7.1-7.3
(m, 5 H), 7.70 (s, 1 H), 7.9-8.0 (m, 1H).

Example 6 CM-Dex-PA-Phe-Gly-AM-drug (1)

Embedded image (In the formula, the portion of the drug carrier to which the pharmaceutical compound is bound via a spacer is described as a repeating unit. However, this notation is a schematic representation for convenience. Should not be interpreted as a compound consisting of

An aqueous solution of CM-dextran polyalcohol (average molecular weight 300K, degree of CM 0.40, concentration 27.8 mg / ml) 33
ml of a solution of 120 mg of the compound obtained in Example 5 and 25 mg of 1-hydroxybenzotriazole (abbreviated as HOBt) in methanol (5 mL).
0 ml) and then 35 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), and then the reaction solution was adjusted to around pH 7.4 with a 1N aqueous sodium hydroxide solution. . After stirring at room temperature for 2 hours, 35 mg of EDC was added, and the mixture was further stirred at room temperature for 20 hours. GPC analysis ｛Column: Tosoh TSK Gel PW-4000XL, eluent: 20% acetonitrile-0.1 M aqueous sodium acetate solution (pH 5)｝ After confirming the completion of the reaction, add 1 N sodium hydroxide
After adjusting to around 11, stirring for 1 hour, Biomax-5
Desalting and low molecular organic compounds were removed using a 0 membrane. The residual solution that does not pass through the membrane is filtered using a Millipore filter (0.
After filtration through 22 (m), lyophilized to give 802 mg of the title compound
I got The content of the drug compound residue of this compound was determined based on the absorbance at 308 nm in water: acetonitrile = 1: 1, and was found to be 5.5%.

Example 7 9H-fluoren-9-ylmethyl 13-([1- [2-amino-6- (4-
[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]
-1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) -7-benzyl-2,5,
8,11-tetraoxo-3,6,9,12-tetraazatridec-1-yl carbamate {Fmoc-Gly-Gly-Phe-Gly-AM-drug (1)} Compound 65 obtained in Example 1-2 mg and Fmoc-Gly-Gly-Phe-OH 9
The same reaction, post-treatment, and purification as in Example 3 were carried out using 3 mg to obtain 123 mg of the title compound. ¹ H NMR (CDCl ₃ ) δ: 2.5-2.6 (m, 4 H), 2.61 (s, 3
H), 3.0-3.1 (m, 1 H), 3.18 (d, 2 H, J = 7.8 Hz),
3.2-3.3 (m, 5 H), 3.8-3.9 (m, 3 H), 3.9-4.0 (m, 5
H), 4.2-4.3 (m, 2 H), 4.4-4.5 (m, 3 H), 4.5-4.6
(m, 1 H), 4.7-4.9 (m, 3 H), 6.02 (dt, 1 H, J = 15.
9, 6.6 Hz), 6.05 (s, 1 H), 6.25 (t, 1 H, J = 8.3 H
z), 6.3-6.4 (m, 3 H), 7.1-7.3 (m, 7 H), 7.38 (t, 2
H, J = 7.3 Hz), 7.5-7.6 (m, 2 H), 7.69 (s, 1 H),
7.73 (d, 2 H, J = 7.3 Hz).

Example 8 2-([2-[(2-aminoacetyl) amino] acetyl] amino) -N
-(2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5 -Methyl-1
H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] -2-oxoethyl) -3-phenylpropanamide ｛H-Gly-Gly-Phe-Gly-AM-drug (1)｝ Using 123 mg of the compound obtained in Example 7, the same reaction as in Example 5,
By performing post-treatment, 71 mg of the title compound was obtained. ¹ H NMR (CDCl ₃ ) δ: 2.5-2.6 (m, 4 H), 2.62 (s, 3
H), 3.17 (d, 2 H, J = 7.8 Hz), 3.2-3.3 (m, 7 H),
3.3-3.4 (m, 1 H), 3.8-3.9 (m, 2 H), 3.9-4.0 (m, 4
H), 4.2-4.3 (m, 2 H), 4.4-4.5 (m, 1 H), 4.5-4.6
(m, 1 H), 4.7-4.9 (m, 3 H), 6.02 (dt, 1 H, J = 15.
9, 6.6 Hz), 6.09 (s, 1 H), 6.24 (t, 1 H, J = 8.3 H
z), 6.3-6.4 (m, 3 H), 7.1-7.3 (m, 5 H), 8.01 (s, 1
H).

Example 9 CM-Dex-PA-Gly-Gly-Phe-Gly-AM-drug (1)

Embedded image

After condensing 130 mg of the compound obtained in Example 8 with 862 mg of CM-dextran polyalcohol in the same manner as in Example 6, post-treatment, purification and lyophilization were carried out in the same manner as in Example 6. This gave 834 mg of the title compound.
The content of the drug compound residue in the present compound was determined by the same method as in Example 6 to be 5.8%.

Example 10 9H-Fluoren-9-ylmethyl 13-([1- [2-amino-6- (4-
[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]
-1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) -7- (sec-butyl)-
2,5,8,11-tetraoxo-3,6,9,12-tetraazatridec-
1-yl carbamate ｛Fmoc-Gly-Gly-Ile-Gly-AM-drug
(1)｝ 110 mg of compound obtained in Example 1-2 and Fmoc-Gly-Gly-Ile-OH
The same reaction, post-treatment and purification as in Example 3 were carried out using 140 mg to give 92 mg of the title compound. ¹ H NMR (CDCl ₃ ) δ: 0.90 (t, 3 H, J = 7.4 Hz), 0.94
(d, 3 H, J = 6.9 Hz), 1.1-1.3 (m, 1 H), 1.5-1.6
(m, 1 H), 1.8-1.9 (m, 1 H), 2.64 (s, 3 H), 2.7-2.8
(m, 4 H), 3.19 (d, 2 H, J = 7.8 Hz), 3.2-3.3 (m,
4 H), 3.8-3.9 (m, 3 H), 3.9-4.0 (m, 3 H), 4.0-4.1
(m, 3 H), 4.2-4.3 (m, 3 H), 4.44 (d, 2H, J = 6.6 H
z), 4.5-4.6 (m, 1 H), 4.7-4.8 (m, 2 H), 4.7-4.9
(m, 3 H), 6.02 (dt, 1 H, J = 15.9, 6.6 Hz), 6.04
(s, 1 H), 6.26 (t, 1 H, J = 8.3 Hz), 6.36 (d, 2 H,
J = 8.3 Hz), 6.37 (d, 1 H, J = 15.9 Hz), 7.2-7.3
(m, 2 H), 7.40 (t, 2 H, J = 7.3 Hz), 7.5-7.6 (m, 2
H), 7.73 (s, 1 H), 7.75 (d, 2 H, J = 7.3 Hz).

Example 11 2-([2-[(2-aminoacetyl) amino] acetyl] amino) -N
-(2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5 -Methyl-1
H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] -2-oxoethyl) -3-methylpentanamide ｛H-Gly-Gly-Ile-Gly-AM-drug (1)｝ Using 240 mg of the compound obtained in Example 10, the same reaction as in Example 5,
By performing post-treatment, 138 mg of the title compound was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.92 (t, 3 H, J = 7.4 Hz), 0.93
(d, 3 H, J = 6.9 Hz), 1.1-1.3 (m, 1 H), 1.5-1.6
(m, 1 H), 1.8-1.9 (m, 1 H), 2.62 (s, 3 H), 2.7-2.8
(m, 4 H), 3.19 (d, 2 H, J = 7.8 Hz), 3.2-3.3 (m,
4 H), 3.39 (d, 2H, J = 1.0 Hz), 3.8-4.0 (m, 6 H),
4.13 (d, 1 H, J = 7.3 Hz), 4.2-4.3 (m, 2 H), 4.5-4.
6 (m, 1 H), 4.76 (d, 2 H, J = 2.7 Hz), 6.00 (dt, 1
H, J = 15.9, 6.6 Hz), 6.01 (s, 1 H), 6.26 (t, 1
H, J = 8.3 Hz), 6.37 (d, 2 H, J = 8.3 Hz), 6.38 (d,
1 H, J = 15.9 Hz), 7.1-7.2 (m, 1 H), 7.75 (s, 1
H).

Example 12 CM-Dex-PA-Gly-Gly-Ile-Gly-AM-drug (1)

Embedded image

After condensing 138 mg of the compound obtained in Example 11 with 987 mg of CM-dextran polyalcohol in the same manner as in Example 6, post-treatment, purification and lyophilization were carried out in the same manner as in Example 6. This gave 1.14 g of the title compound.
The content of the drug compound residue in the present compound was determined by the same method as in Example 6 to be 6.1%.

Example 13 9H-Fluoren-9-ylmethyl 13-([1- [2-amino-6- (4-
[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]
-1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) -7-isopropyl-
2,5,8,11-tetraoxo-3,6,9,12-tetraazatridec-
1-yl carbamate ｛Fmoc-Gly-Gly-Val-Gly-AM-drug
(1)｝ 190 mg of the compound obtained in Example 1-2 and Fmoc-Gly-Gly-Val-OH
The same reaction, post-treatment and purification as in Example 3 were carried out using 250 mg to give 233 mg of the title compound. ¹ H NMR
(CDCl ₃ ) δ: 0.98 (d, 6 H, J = 5.6 Hz), 2.1-2.2
(m, 1 H), 2.61 (s, 3 H), 2.7-2.8 (m, 4 H), 3.19 (d,
2 H, J = 7.8 Hz), 3.2-3.3 (m, 4 H), 3.8-3.9 (m, 4
H), 3.9-4.0 (m, 2 H), 4.0-4.1 (m, 3 H), 4.2-4.3
(m, 3 H), 4.43 (d, 2 H, J = 6.6 Hz), 4.5-4.6 (m, 1
H), 4.7-4.8 (m, 2 H), 6.03 (dt, 1H, J = 15.9, 6.6
Hz), 6.04 (s, 1 H), 6.26 (t, 1 H, J = 8.3 Hz), 6.
38 (d, 2 H, J = 8.3 Hz), 6.39 (d, 1 H, J = 15.9 H
z), 7.27 (t, 2 H, J = 7.3 Hz), 7.39 (t, 2 H, J =
7.3 Hz), 7.58 (d, 2 H, J = 7.3 Hz), 7.73 (s, 1 H),
7.75 (d, 2 H, J = 7.3 Hz).

Example 14 2-([2-[(2-aminoacetyl) amino] acetyl] amino) -N
-(2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5 -Methyl-1
H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] -2-oxoethyl) -3-methylbutanamide ｛H-Gly-Gly-Val-Gly-AM-drug (1)反 応 Using 311 mg of the compound obtained in Example 13, the same reaction as in Example 5,
By performing post-treatment, 237 mg of the title compound was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.96 (d, 6 H, J = 5.6 Hz), 2.2-
2.3 (m, 1 H), 2.62 (s, 3 H), 2.7-2.8 (m, 4 H), 3.17
(d, 2 H, J = 7.8 Hz), 3.2-3.3 (m, 4 H), 3.8-3.9
(m, 4 H), 3.9-4.0 (m, 2 H), 4.0-4.1 (m, 3 H), 4.2-
4.3 (m, 2 H), 4.5-4.6 (m, 1 H), 4.7-4.8 (m, 1 H),
4.8-4.9 (m, 1 H), 5.0-5.1 (m, 1 H), 6.02 (dt, 1 H,
J = 15.9, 6.6 Hz), 6.06 (s, 1 H), 6.24 (t, 1 H, J
= 8.3 Hz), 6.3-6.4 (m, 3 H), 7.72 (s, 1 H).

Example 15 CM-Dex-PA-Gly-Gly-Val-Gly-AM-drug (1)

Embedded image

Using 237 mg of the compound obtained in Example 14 and condensing with 1.724 g of CM-dextran polyalcohol in the same manner as in Example 6, post-treatment, purification and lyophilization were carried out in the same manner as in Example 6. This gave 1.88 g of the title compound.
The content of the drug compound residue in the present compound was determined by the same method as in Example 6 to be 6.0%.

Example 16 9H-fluoren-9-ylmethyl (1S) -1-[(2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3 , 5-Difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl-1H-pyrazole-1
-Yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] -2-oxoethyl) amino] carbonyl] -3- (methylsulfanyl) propylcarbamate ｛Fmoc-Met-Gl
y-AM-drug (1)｝ Using 100 mg of the compound obtained in Example 1-2 and 131 mg of Fmoc-Met-OH, the same reaction, post-treatment and purification as in Example 3 were performed to give the title compound. 196 mg were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.22 (m, 5H), 2.52-2.58 (m,
2 H), 2.61 (s, 3 H), 2.73-2.75 (m, 4 H), 3.21-3.28
(m, 6 H), 3.74-5.08 (m, 13 H), 6.01-6.07 (m, 3
H), 6.24 (tt, 1 H, J = 8.8 Hz, 2.2 Hz), 6.36 (dd,
2 H, J = 8.8 Hz, 2.2 Hz), 6.40 (d, 1 H, J = 16.1 H
z), 7.27-7.29 (m, 2H), 7.37 (t, 2H, J = 7.6 Hz),
7.54 (d, 2 H, J = 7.6 Hz), 7.70 (d, 2 H, J = 7.6 H
z), 7.75 (s, 1 H).

Example 17 (2S) -2-amino-N- (2-[[([1- [2-amino-6- (4-[(E) -3- [4-
(3,5-Difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] -2- (Oxoethyl) -4- (methylsulfanyl) butanamide ｛H-Met-
Gly-AM-drug (1)｝ Dissolve 196 mg of the compound obtained in Example 16 in 1,4-dioxane 20 ml, add piperidine 2 ml, and DMF 1 ml, and add
Stirred for minutes. After evaporating the solvent, the residue was subjected to silica gel column chromatography, developed in a lower layer of chloroform: methanol: water = 7: 3: 1, and the fraction containing the desired product was concentrated to obtain 117 mg of the title compound. Was. ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.89 (m, 1 H), 2.10 (s, 3
H), 2.17-2.21 (m, 1 H), 2.63-2.64 (m, 9 H), 3.18-3.
24 (m, 6 H), 3.61-3.64 (m, 1H), 3.93-3.97 (m, 4 H),
4.23-4.27 (m, 2 H), 4.55-4.58 (m, 1 H), 4.76-4.78
(m, 2 H), 6.05 (dt, 1 H, J = 15.9 Hz, 6.9 Hz), 6.1
0 (s, 1 H), 6.24 (dt, 1 H, J = 8.8 Hz, 2.2 Hz), 6.
36 (dd, 2 H, J = 8.8 Hz, 2.2 Hz), 6.40 (d, 1 H, J
= 16.9 Hz), 7.73 (s, 1 H).

Example 18 9H-fluoren-9-ylmethyl (7S) -13-([1- [2-amino-6
-(4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl-1H-pyrazol-1-yl
l) -4-pyrimidinyl] -3-azetidinyl] oxy) -7- [2- (methylsulfanyl) ethyl] -2,5,8,11-tetraoxo-3,
6,9,12-Tetraazatridec-1-yl carbamate ｛Fmoc
-Gly-Gly-Met-Gly-AM-drug (1)｝ 117 mg of compound obtained in Example 17 and 118 mg of Fmoc-Gly-Gly-OH
The same reaction, post-treatment, and purification as in Example 3 were performed using to obtain 182 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.22 (m, 5H), 2.48-2.52 (m,
2 H), 2.55-2.68 (m, 7H), 3.21-3.28 (m, 6 H), 3.82
-4.81 (m, 17 H), 5.98-6.05 (m, 3 H), 6.25 (dt, 1
H, J = 8.8 Hz, 1.9 Hz), 6.36 (dd, 2 H, J = 8.6 Hz,
1.9 Hz), 6.39 (d, 1 H, J = 17.1 Hz), 7.24-7.29
(m, 2H), 7.36 (t, 2 H, J = 7.3 Hz), 7.53 (d, 2 H, J
= 9.3 Hz), 7.70-7.73 (m, 3 H).

Example 19 (2S) -2-([2-[(2-aminoacetyl) amino] acetyl] amino) -N- (2-[[([1- [2-amino-6- (4- [(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl ] Oxy) methyl] amino] -2-oxoethyl) -4-
(Methylsulfanyl) butanamide ｛H-Gly-Gly-Met-Gly-
AM-drug (1)｝ Using compound 182 mg obtained in Example 18, similar reaction to Example 17,
By performing the post-treatment, 135 mg of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.20 (m, 5 H), 2.45-2.70 (m,
9 H), 3.11-3.27 (m, 6H), 3.58-4.78 (m, 14 H), 5.9
4-6.07 (m, 3 H), 6.23 (t, 1 H, J = 8.8 Hz), 6.33-6.
36 (m, 3 H), 7.71 (s, 1 H).

Example 20 CM-Dex-PA-Gly-Gly-Met-Gly-AM-drug (1)

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After condensing 135 mg of the compound obtained in Example 19 with 870 mg of CM-dextran polyalcohol in the same manner as in Example 6, post-treatment, purification and lyophilization were carried out in the same manner as in Example 6. This gave 956 mg of the title compound.
The content of the drug compound residue in this compound was determined by the same method as in Example 6 and found to be 4.7%.

Example 21 tert-butyl 2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl) oxy] methyl] amino])-2-oxoethyl
(Methyl) carbamate << Boc-Sar-AM-drug (1) >> Example 21-1 ([2-[(tert-butoxycarbonyl) (methyl) amino] acetyl] amino) methyl acetate Boc-sarcosylsylglycine 4.11 g And lead tetraacetate ｛Pb
The same reaction, post-treatment and purification as in Example 1-1 were carried out using 4.20 g of (OAc) ₄ to give 3.20 g of the title compound. ¹ H NMR (CDCl ₃ ) δ: 1.47 (s, 9 H), 2.07 (s, 3 H),
2.93 (s, 3 H), 3.88 (brs, 2 H), 5.26 (d, 2 H, J =
7 Hz).

Example 21-2 tert-butyl 2-([[(1-benzhydryl-3-azetidinyl)
Oxy] methyl] amino) -2-oxyethyl (methyl) carbamate 479 mg of 1-benzhydryl-3-azetidinol and Example 21
Using 520 mg of the compound obtained in -1, the same reaction, post-treatment and purification as in Example 1-3 were carried out to give the title compound
223 mg were obtained. ¹ H NMR (CDCl ₃ ) δ: 1.43 (s, 9 H), 2.86 (brs, 3 H),
2.91 (dd, 2 H, J = 6 Hz, 9 Hz), 3.48 (dd, 2 H, J =
7 Hz, 9 Hz), 3.82 (s, 2 H), 4.26 (m, 1 H), 4.33
(s, 1 H), 4.70 (d, 2 H, J = 7 Hz), 7.15-7.40 (m, 1
0 H).

Example 21-3 tert-butyl 2-[[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl) oxy] methyl] amino])-2-oxoethyl
(Methyl) carbamate {Boc-Sar-AM-drug (1)} After dissolving 223 mg (0.51 mmol) of the compound obtained in Example 21-2 in 50 ml of ethanol, 10% palladium-carbon (50% water-containing) was dissolved. ) 200 mg, and subjected to catalytic hydrogenation under pressure (5 kg / cm ² ) for 16 hours. After removing the insoluble matter by filtration and concentrating the filtrate to dryness, the residue was dissolved in dimethylformamide (20 ml), and 4-chloro-6- (4-[(E) -3- [4- (3,5-difluoro After adding 183 mg of phenyl) -1-piperazinyl] -1-propenyl] -5-methyl-1H-pyrazol-1-yl) -2-pyrimidinylamine and 0.057 ml of triethylamine, the mixture was stirred at 80 ° C. for 48 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was subjected to preparative thin-layer chromatography, and developed with a mixed solvent of 10% methanol-chloroform to obtain 137 mg of the title compound. ¹ H NMR (CDCl ₃ ) δ: 1.47 (s, 9 H), 2.61-2.64 (m, 7
H), 2.96 (s, 3 H), 3.18 (d, 2 H, J = 6.1 Hz), 3.21-
3.24 (m, 4 H), 3.88 (s, 2 H), 3.95 (dd, 2 H, J = 9.
8 Hz, 3.8 Hz), 4.24-4.28 (m, 2 H), 4.56-4.61 (m, 1
H), 4.74-4.79 (m, 4 H), 6.03 (dt, 1H, J = 15.9 H
z, 7.8 Hz), 6.11 (s, 1 H), 6.24 (dt, 1H, J = 8.8 H
z, 2.2 Hz), 6.35-6.39 (m, 3 H), 7.73 (s, 1 H).

Example 22 2-amino-N-[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]- 1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] -2- (methylamino) acetamide ｛H-Sar-AM-drug (1) <4> To 137 mg of the compound obtained in Example 21-3 was added 10 ml of a 5% trifluoroacetic acid-methylene chloride solution under ice-cooling, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, developed in the lower layer of chloroform: methanol: water = 20: 3: 1, and the fraction containing the target compound was concentrated to give 58 mg of the title compound
I got ¹ H NMR (CDCl ₃ ) δ: 2.46 (s, 3 H), 2.48 (s, 3 H), 2.6
8-2.72 (m, 4 H), 3.18 (d, 2 H, J = 6.1 Hz), 3.25-3.
28 (m, 4H), 3.34 (s, 2H), 3.95-3.97 (m, 2H, J =
9.8 Hz, 3.8 Hz), 4.25-4.29 (m, 2 H), 4.58-4.72 (m,
1H), 4.78 (d, 2 H, J = 8.3 Hz), 4.80-4.85 (m, 2
H), 6.05 (dt, 1H, J = 17.1 Hz, 7.5 Hz), 6.11 (s, 1
H), 6.26 (t, 1 H, J = 8.3 Hz), 6.35-6.42 (m, 3
H), 7.74 (s, 1 H).

Example 23 9H-Fluoren-9-ylmethyl (7S) -13-([1- [2-amino-6
-(4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl-1H-pyrazol-1-yl)
-4-pyrimidinyl] -3-azetidinyl] oxy) -7-benzyl-9-methyl-8-methylene-2,5,11-trioxo-3,6,9,12-
Tetraazatridec-1-yl carbamate ｛Fmoc-Gly-Gl
y-Phe-Sar-AM-drug (1)｝ 58 mg of the compound obtained in Example 22 and Fmoc-Gly-Gly-Phe-OH 100
The same reaction, post-treatment and purification as in Example 3 were carried out using mg to give 43 mg of the title compound. _{^{1 H NMR (CDCl 3) δ}} : 2.58-2.69 (m, 10 H), 3.08-3.25
(m, 8 H), 3.69-4.74 (m, 16 H), 5.97-6.07 (m, 2 H, C
H = C H CH ₂ ), 6.24 (t, 1 H, J = 8.6 Hz), 6.31-6.36 (m,
3 H), 7.16-7.73 (m, 9 H).

Example 24 2-amino-N- [2-([(1S) -2-[(2-[[([1- [2-amino-6- (4-
[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]
-1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] -2
-Oxoethyl) (methyl) amino] -1-benzyl-2-propenyl] amino) -2-oxoethyl] acetamide {H-Gly-Gly-
Phe-Sar-AM-drug (1) 43 mg of the compound obtained in Example 23 was dissolved in 6 ml of DMF, 4 ml of piperidine was added, and the mixture was stirred at room temperature for 2 days. After evaporating the solvent under reduced pressure, HPLC ｛column: CAPCELL PAK C18, eluent: 40% (1/2 = MeOH / CH ₃ CN) /0.1% TFA aqueous solution, flow rate: 8
Purification using ml / min｝ gave the title compound 16
mg was obtained. ¹ H NMR (CDCl ₃ ) δ: 2.61-2.64 (m, 7 H, Me), 2.79 (s,
3 H), 2.79-3.10 (m, 2H), 3.16-3.22 (m, 6 H), 3.40
(s, 2 H), 3.84-4.69 (m, 10 H), 4.78-4.80 (m, 2 H),
5.99-6.09 (m, 2 H), 6.24 (dt, 1 H, J = 8.8 Hz, 2.
2 Hz), 6.34-6.37 (m, 3 H), 7.71 (s, 1 H).

Example 25 CM-Dex-PA-Gly-Gly-Phe-Sar-AM-drug (1)

Embedded image

After condensing with 16 mg of the compound obtained in Example 24 and 92 mg of CM-dextran polyalcohol in the same manner as in Example 6, post-treatment, purification and lyophilization were carried out in the same manner as in Example 6. This gave 103 mg of the title compound. The content of the drug compound residue in the present compound was determined in the same manner as in Example 6 to be 4.4%.

Example 26 tert-butyl 1-([[[[[1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl] oxy) methyl] amino] carbonyl) -2-methylbutylcarbamate {Boc-Ile-AM-drug (1)} Example 26-1 ([2-[(tert-butoxycarbonyl) amino] -3-methylpentane Noyl] amino) methyl acetate 4.26 g of Boc-isoleucylglycine and lead tetraacetate ｛Pb
The same reaction, post-treatment and purification as in Example 1-1 were performed using (OAc) ₄ ｝ 8.14 g to give the title compound (3.64 g). ¹ H NMR (CDCl ₃ ) δ: 0.91 (t, 3 H, J = 7.3 Hz), 0.93
(d, 3 H, J = 6.8 Hz), 1.05-1.20 (m, 1 H), 1.35-1.5
5 (m, 1H), 1.44 (s, 9H), 1.85-2.00 (m, 1H), 2.06
(s, 3 H), 3.95-4.05 (m, 1 H), 4.95-5.05 (m, 1 H),
5.20-5.30 (m, 2 H), 7.00-7.10 (m, 1 H).

Example 26-2 tert-butyl 1-([[(1-benzhydryl-3-azetidinyloxy) methyl] amino] carbonyl) -2-methylbutylcarbamate 1-benzhydryl-3-azetidinol 1.08 g and example 26−
Using 1.36 g of the compound obtained in 1, the same reaction as in Example 1-3,
After work-up and purification, the title compound 690
mg was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.86 (t, 3 H, J = 7.3 Hz), 0.91
(d, 3 H, J = 6.8 Hz), 1.00-1.15 (m, 1 H), 1.30-1.5
0 (m, 1 H), 1.40 (s, 9 H), 1.80-1.95 (m, 1H), 2.91
(dd, 2 H, J = 9 Hz, 6 Hz), 3.47 (dd, 2 H, J = 9 H
z, 6 Hz), 3.91 (dd, 1 H, J = 9 Hz, 6 Hz), 4.24-4.30
(m, 1 H), 4.33 (s, 1 H), 4.66 (d, 2 H, J = 7 Hz),
4.90-5.00 (m, 1 H), 6.70-6.80 (m, 1 H), 7.10-7.40
(m, 10H).

Example 26-3 tert-butyl 1-([[[[[1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl] oxy) methyl] amino] carbonyl) -2-methylbutylcarbamate {Boc-Ile-AM-drug (1)} 335 g of the compound obtained in Example 26-2 was dissolved in 20 ml of ethanol, and then 10% 300 mg of palladium-carbon (containing 50% water) was added, and contact hydrogenation was performed under pressure (5 kg / cm ² ) for 20 hours. After removing insoluble matter by filtration and concentrating the filtrate, ethyl acetate was added to the residue and the mixture was stirred for 1 hour. The precipitate was collected by filtration, dissolved in a mixed solvent of methanol and chloroform (1: 9), and washed with a mixed solution of a saturated saline solution and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a white solid.
1 mg was obtained. 141 mg of the obtained solid and 4-chloro-6- (4-
[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]
-1-propenyl] -5-methyl-1H-pyrazol-1-yl) -2-pyrimidinylamine (199 mg) in dimethylformamide (10 ml)
And add 0.063 ml of triethylamine.
Stirred at C for 36 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, developed with a mixed solvent of methanol and chloroform (2:98), and the fraction containing the desired product is concentrated. Thereby, 205 mg of the title compound was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.93 (t, 3 H, J = 7.6 Hz), 0.95
(d, 3 H, J = 6.8 Hz), 1.05-1.25 (m, 1 H), 1.40-1.6
0 (m, 1 H), 1.45 (s, 9 H), 1.90-2.00 (m, 1H), 2.63
(t, 4 H, J = 5 Hz), 2.65 (s, 3 H), 3.18 (d, 2 H,
J = 7 Hz), 3.23 (t, 4 H, J = 5 Hz), 3.90-4.00 (m,
3 H), 4.20-4.30 (m, 2 H), 4.55-4.65 (m, 1 H), 4.70-
4.85 (m, 4 H), 4.90-5.00 (m, 1 H), 6.03 (dt, 1 H,
J = 16Hz, 7 Hz), 6.12 (s, 1 H), 6.25 (tt, 1 H, J =
9 Hz, 2 Hz), 6.30-6.45 (m, 3 H), 6.75-6.85 (m, 1
H), 7.73 (s, 1 H).

Example 27 2-amino-N-[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]- 1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] -3-methylpentanamide ｛HI
le-AM-drug (1)｝ Using 481 mg of the compound obtained in Example 26-3, the same reaction, post-treatment and purification as in Example 2 were carried out to give the title compound 30
7 mg were obtained. ¹ H NMR (CDCl ₃ ) δ: 0.92 (t, 3 H, J = 7.3 Hz), 0.99
(d, 3 H, J = 6.8 Hz), 1.05-1.20 (m, 1 H), 1.25-1.4
5 (m, 1 H), 2.00-2.15 (m, 1 H), 2.63 (t, 4H, J = 5
Hz), 2.65 (s, 3 H), 3.18 (d, 2 H, J = 7 Hz), 3.23
(t, 4 H, J = 5 Hz), 3.90-4.00 (m, 2 H), 4.20-4.40
(m, 3 H), 4.55-4.65 (m, 1 H), 4.70-4.90 (m, 4 H),
6.03 (dt, 1 H, J = 16 Hz, 7 Hz), 6.11 (s, 1 H), 6.
24 (tt, 1 H, J = 9 Hz, 2 Hz), 6.30-6.45 (m, 3 H),
7.74 (s, 1 H), 8.15-8.25 (m, 1 H).

Example 28 9H-Fluoren-9-ylmethyl 2-([2-[(2S) -2-([[(1R, 2R)
-1-([[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5 -Methyl-1
H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] carbonyl) -2-methylbutyl] amino] carbonyl) pyrrolidinyl] -2-oxoethyl]
Amino) -2-oxoethyl carbamate ｛Fmoc-Gly-Gly-
Pro-Ile-AM-drug (1)｝ Compound 303 mg obtained in Example 27 and Fmoc-Gly-Gly-Pro-OH 21
The same reaction, post-treatment and purification as in Example 3 were performed using 9 mg to obtain 368 mg of the title compound. ¹ H-NMR (C
DCl ₃ ) δ: 0.86-0.92 (m, 6 H), 1.10-2.18 (m, 7 H),
2.61-2.64 (m, 7H), 3.16-3.22 (m, 6H), 3.48-3.53
(m, 1 H), 3.67-3.71 (m, 1 H), 3.82-4.31 (m, 10 H),
4.40 (t, 1 H, J = 7.3 Hz), 4.52-4.61 (m, 3 H), 4.
80-4.89 (m, 4 H), 6.02 (dt, 1H, J = 15.9 Hz, 5.6 H
z), 6.12 (s, 1 H), 6.24 (t, 1 H, J = 8.8 Hz), 6.34
-6.37 (m, 3 H), 7.28 (t, 2H, J = 7.4 Hz), 7.37 (t,
2H, J = 7.4 Hz), 7.52-7.57 (m, 2 H), 7.71-7.75
(m, 3 H).

Example 29 (2S) -1- [2-[(2-aminoacetyl) amino] acetyl] -N-
[(1R, 2R) -1-([[[[1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]- 1-propenyl] -5-
Methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] carbonyl) -2-methylbutyl] -2-pyrrolidinecarboxamide {H-Gly-Gly-
Pro-Ile-AM-drug (1)｝ Using 368 mg of the compound obtained in Example 28, the same reaction as in Example 17,
By performing post-treatment, 178 mg of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.86-0.92 (m, 6 H), 1.09-1.52 (m,
2 H), 1.98-2.21 (m, 5H), 2.61-2.64 (m, 7 H), 3.16
-3.22 (m, 6 H), 3.38 (s, 2 H), 3.48-3.81 (m, 2
H), 3.78-3.94 (m, 4 H), 4.08-4.15 (m, 1 H), 4.17-
4.25 (m, 2 H), 4.31 (t, 1 H, J = 6.8 Hz), 4.52-4.5
8 (m, 2 H), 4.68-4.88 (m, 2 H), 5.08-5.12 (m, 2
H), 6.02 (dt, 1H, J = 15.9 Hz, 5.8 Hz), 6.08 (s, 1
H), 6.24 (t, 1 H, J = 8.8 Hz), 6.34-6.37 (m, 3 H),
7.72 (s, 1 H).

Example 30 CM-Dex-PA-Gly-Gly-Pro-Ile-AM-drug (1)

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Using 178 mg of the compound obtained in Example 29 and condensing it with 1.18 g of CM-dextran polyalcohol in the same manner as in Example 6, post-treatment, purification and lyophilization were carried out in the same manner as in Example 6. This gave 1.34 g of the title compound.
The content of the drug compound residue in the present compound was determined by the same method as in Example 6 to be 7.3%.

Example 31 tert-butyl 1-([[([[1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl] oxy) methyl] amino] carbonyl) -3-methylbutylcarbamate {Boc-Leu-AM-drug (1)} Example 31-1 ([2-[(tert-butoxycarbonyl) amino] -4-methylpentane Noyl] amino) methyl acetate Boc-leucylglycine 10.95 g and lead tetraacetate Pb (OA
c) _4} with 20.9 g, Example 1-1 the same reaction, after-treatment, and by performing purification to afford the title compound 6.58 g. ¹ H NMR (CDCl ₃ ) δ: 0.93 (d, 3 H, J = 6 Hz), 0.94
(d, 3 H, J = 6 Hz), 1.44 (s, 9 H), 1.40-1.75 (m, 3
H), 2.06 (s, 3 H), 4.05-4.15 (m, 1 H), 4.75-4.85
(m, 1 H), 5.20-5.30 (m, 2 H), 7.15-7.25 (m, 1 H).

Example 31-2 tert-butyl 1-([[(1-benzhydryl-3-azetidinyloxy) methyl] amino] carbonyl) -3-methylbutylcarbamate 3.38 g of 1-benzhydryl-3-azetidinol and the example 31
Using 2.68 g of the compound obtained in -1, the same reaction, post-treatment and purification as in Example 1-3 were carried out to give the title compound
1.20 g were obtained. ¹ H NMR (CDCl ₃ ) δ: 0.89 (d, 3 H, J = 6 Hz), 0.90
(d, 3 H, J = 6 Hz), 1.35-1.50 (m, 1 H), 1.40 (s, 9
H), 2.90-2.95 (m, 2 H), 3.45-3.55 (m, 2 H), 4.00-
4.10 (m, 1 H), 4.20-4.30 (m, 1 H), 4.33 (s, 1 H),
4.65-4.70 (m, 2 H), 4.70-4.80 (br, 1 H), 6.75-6.85
(m, 1 H), 7.10-7.50 (m, 10 H).

Example 31-3 tert-butyl 1-([[[[[1- [2-amino-6- (4-[(E) -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-propenyl]-
5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-
Azetidinyl] oxy) methyl] amino] carbonyl) -3-methylbutylcarbamate {Boc-Leu-AM-drug (1)} 1.20 g of the compound obtained in Example 31-2 was dissolved in 50 ml of ethanol, and then dissolved in 10 ml of 10%. 600 mg of palladium-carbon (containing 50% water) was added, and catalytic hydrogenation was performed under pressure (5 kg / cm ² ) for 20 hours. The insolubles were removed by filtration, the filtrate was concentrated, ethyl acetate was added to the residue, and the mixture was stirred for 1 hour, and the precipitate was collected by filtration to obtain 490 mg of a white solid. The resulting solid
288 mg and 4-chloro-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl
-1H-pyrazol-1-yl) -2-pyrimidinylamine 326 mg
Was dissolved in 9 ml of dimethylformamide, and 0.153 ml of triethylamine was added, followed by stirring at 80 ° C. for 36 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution. The organic layer is dried over anhydrous sodium sulfate,
After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and methanol: chloroform (2: 9
8) The mixture was developed with a mixed solvent, and the fraction containing the desired compound was concentrated to obtain 327 mg of the title compound. ¹ H NMR (CDCl ₃ ) δ: 0.94 (d, 3 H, J = 6 Hz), 0.96
(d, 3 H, J = 6 Hz), 1.40-1.60 (m, 1 H), 1.49 (s, 9
H), 1.60-1.80 (m, 2 H), 2.60-2.70 (m, 4 H), 2.65
(s, 3 H), 3.19 (d, 2 H, J = 7 Hz), 3.24 (t, 4 H, J
= 5 Hz, 3.90-4.00 (m, 2 H), 4.05-4.15 (m, 1 H),
4.20-4.30 (m, 2 H), 4.55-4.60 (m, 1 H), 4.70-4.90
(m, 5 H), 6.03 (dt, 1 H, J = 16 Hz, 7 Hz), 6.12
(s, 1 H), 6.25 (tt, 1 H, J = 9 Hz, 2 Hz), 6.35-6.40
(m, 2 H), 6.38 (d, 1 H, J = 16 Hz), 6.90-7.00 (m,
1 H), 7.73 (s, 1 H).

Example 32 2-Amino-N-[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl]- 1-propenyl] -5-methyl-1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl] oxy) methyl] -4-methylpentanamide ｛HL
eu-AM-drug (1)｝ Using 327 mg of the compound obtained in Example 31-3, the same reaction, work-up and purification as in Example 2 were carried out to give the title compound 15
3 mg was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.95 (d, 3 H, J = 6 Hz), 0.99
(d, 3 H, J = 6 Hz), 1.30-1.50 (m, 1 H), 1.70-1.85
(m, 2 H), 2.60-2.70 (m, 4 H), 2.65 (s, 3 H), 3.19
(d, 2 H, J = 7 Hz), 3.20-3.30 (m, 4 H), 3.43 (dd,
1 H, J = 10 Hz, 3 Hz), 3.90-4.00 (m, 2 H), 4.20-4.3
0 (m, 2 H), 4.55-4.65 (m, 1 H), 4.70-4.90 (m, 4
H), 6.04 (dt, 1 H, J = 16 Hz, 7 Hz), 6.12 (s, 1
H), 6.24 (t, 1H, J = 9 Hz), 6.30-6.45 (m, 3 H), 7.
74 (s, 1 H), 8.10-8.25 (m, 1 H).

Example 33 9H-Fluoren-9-ylmethyl 2-([2-[(2S) -2-([[(1S) -1-
([[[([1- [2-Amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -5-methyl- 1H-
Pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinyl]
Oxy) methyl] amino] carbonyl) -2-methylbutyl] amino] carbonyl) pyrrolidinyl] -2-oxoethyl] amino) -2-oxoethylcarbamate ｛Fmoc-Gly-Gly-Pro-
Leu-AM-drug (1)｝ 208 mg of compound obtained in Example 32 and Fmoc-Gly-Gly-Pro-OH 15
The same reaction, post-treatment and purification as in Example 3 were carried out using 0 mg to give 228 mg of the title compound. ¹ H NMR (CDCl ₃ ) δ: 0.88 (d, 3 H, J = 6.4 Hz), 0.93
(d, 3 H, J = 6.4 Hz), 1.58-1.85 (m, 3 H), 1.93-2.2
2 (m, 4 H), 2.58-2.67 (m, 7 H), 3.16-3.21 (m, 6 H),
3.53-3.68 (m, 2 H), 3.82-5.02 (m, 16 H), 5.99-6.0
8 (m, 3 H), 6.24 (t, 1 H, J = 8.8 Hz), 6.34-6.37
(m, 3H), 7.24-7.28 (m, 2H), 7.36 (t, 2H, J = 7.6
Hz), 7.54 (d, 2 H, J = 7.6 Hz), 7.71 (s, 1 H) 7.72
(d, 2 H, J = 7.6 Hz).

Example 34 (2S) -1- [2-[(2-aminoacetyl) amino] acetyl] -N-
[(1S) -1-([[([1- [2-amino-6- (4-[(E) -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1- Propenyl] -5-methyl-1H-pyrazol-1-yl) -4- 4-pyrimidinyl] -3-azetidinyl] oxy) methyl] amino] carbonyl) -2-methylbutyl] -2-pyrrolidinecarboxamide ｛H-Gly-Gly- P
ro-Leu-AM-drug (1)｝ Using 228 mg of the compound obtained in Example 33, the same reaction as in Example 17,
By performing the post-treatment, 140 mg of the title compound was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.90 (d, 3 H, J = 6.6 Hz), 0.95
(d, 3 H, J = 6.5 Hz), 1.58-1.85 (m, 3 H), 1.93-2.3
8 (m, 4 H), 2.61-2.63 (m, 7 H), 3.17-3.23 (m, 6 H),
3.30 (s, 2 H), 3.58 (dd, 1 H, J = 17.1 Hz, 7.5 H
z), 3.76 (dd, 1 H, J = 15.6 Hz, 5.6 Hz), 3.86-4.95
(m, 13 H), 6.03 (dt, 1 H, J = 15.9 Hz, 6.8 Hz), 6.
09 (s, 1 H), 6.24 (tt, 1 H, J = 8.8 Hz, 2.2 Hz),
6.35-6.39 (m, 3 H), 7.72 (s, 1 H).

Example 35 CM-Dex-PA-Gly-Gly-Pro-Leu-AM-drug (1)

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After condensing 140 mg of the compound obtained in Example 34 with 929 mg of CM-dextran polyalcohol in the same manner as in Example 6, post-treatment, purification and lyophilization were carried out in the same manner as in Example 6. This gave 986 mg of the title compound.
The content of the drug compound residue in the present compound was determined in the same manner as in Example 6 to be 3.6%.

Test Example 1 Release of Drug Compound from DDS Compound The test compound was dissolved (500 μg / ml) in Meth A homogenate at 40 ° C., in a buffer, or in mouse serum at 37 ° C.
1- [2-amino-6- (4-[(E) -3- [4- (3,
5-Difluorophenyl) -1-piperazinyl] -1-propenyl] -1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinol (drug (1)) was quantified. Table 2 shows the test results. The tested compounds showed a peptide sequence-dependent drug release rate in the weakly acidic Meth A homogenate, and released little drug in the weakly acidic buffer and mouse serum. In contrast, Comparative Compound A: CM-Dex-PA-Ile
-Drug (1) and Comparative compound B: CM-Dex-PA-Gly-Gly-Phe-Gly
-PABC-drug (1) (PABC stands for paraaminobenzyloxycarbonyl linker: Dubowchik, GM, et al., JB
ioorg. Med. Chem. Lett., 8, 3347, 1998) showed high release rates in weakly acidic buffers and in mouse serum.

[0104]

Embedded image

[0105]

[Table 2]

Test Example 2: Antitumor activity of DDS compound Meth A cells (Murine fibrosarcoma Meth A) were transplanted into BALB / c mice to produce Meth A tumor-bearing mice.
On the day, the drug was given a single intravenous tail vein. Tumor weight was measured on day 21 to assess tumor growth inhibitory effect and toxicity. Table 3 shows the results. In the table, * indicates the group judged to have a significant difference by Dunnett's test (*** P <0.001, ** P0.01), and the dose is shown in terms of the weight of anhydrous free base of drug (1). Was. IR indicates the reduction ratio of the tumor. The DDS compound of the present invention exerts a tumor reducing effect in a dose-dependent manner, and the drug (1)
It is apparent that the occurrence of diarrhea, which is a side effect, is avoided as compared with the case where the drug itself is used.

[0107]

[Table 3]

[0108]

EFFECT OF THE INVENTION The DDS compound of the present invention has excellent stability in serum, and can selectively transfer a pharmaceutical compound as an active ingredient to a tumor site or the like.
Side effects can be reduced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 35/00 A61P 35/00 C07K 5/103 ZNA C07K 5/103 ZNA (72) Inventor Hiroyuki Naito Tokyo 1-16-13 Kita-Kasai, Edogawa-ku 1st Pharmaceutical Co., Ltd. Tokyo Research and Development Center (72) Inventor Kenshi Hirotani 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 1st Pharmaceutical Co., Ltd. Tokyo Research and Development Center F Terms (reference) 4C076 AA95 CC04 CC27 EE30 EE41 EE59 FF36 4C086 AA01 AA02 AA03 BC42 GA07 MA03 MA05 MA07 MA08 NA05 NA06 NA13 ZB11 ZB26 4H045 AA30 BA13 EA22 EA28

Claims (13)

[Claims] 1. The following formula (I): AWN (R ¹ ) -C (R ² ) (R ³ ) -OQ (where A represents a polymer which is a drug carrier; W represents formula (I)
A spacer containing one amino acid residue bonded to the nitrogen atom at the C-terminus or an oligo composed of two to eight peptide-bonded amino acid residues bonded to the nitrogen atom at the C-terminus in formula (I) R represents a spacer containing a peptide residue;
¹ , R ² and R ³ each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, a carboxyl group or an alkoxycarbonyl group, and R ¹ , R ² , And R ³ may combine with each other to form a 4- to 8-membered ring;
Q represents a residue of a pharmaceutical compound having a hydroxyl group). 2. The DDS compound according to claim 1, wherein the drug carrier is a polysaccharide derivative having a carboxyl group. 3. The DDS compound according to claim 1, wherein W is a spacer containing an oligopeptide residue composed of 2 to 8 amino acid residues bonded to a peptide. 4. The DDS compound according to claim ¹ , wherein R ¹ , R ² and R ³ are hydrogen atoms. 5. The DDS compound according to claim 2, wherein the polysaccharide derivative having a carboxyl group is carboxy C _1-4 alkyl dextran polyalcohol. 6. The dextran polyalcohol constituting the carboxy C _1-4 alkyl dextran polyalcohol is a dextran polyalcohol obtained by treating dextran under conditions under which substantially complete polyalcoholization is possible. 6. The DDS compound according to 5. 7. The DDS compound according to claim 5, wherein the carboxy C _1-4 alkyl dextran polyalcohol is carboxymethyl dextran polyalcohol. 8. The DDS compound according to claim 1, wherein the pharmaceutical compound is an antitumor agent or an anti-inflammatory agent. 9. The method of claim 1, wherein the pharmaceutical compound is 1- [2-amino-6- (4-[(E) -3-
The DDS compound according to claim 8, which is [4- (3,5-difluorophenyl) -1-piperazinyl] -1-propenyl] -1H-pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinol. 10. The DDS compound according to claim 9, wherein W is -Gly-Gly-Phe-Gly-. 11. The following formula (II): PZN (R ¹ ) -C (R ² ) (R ³ ) -OQ (wherein P represents a hydrogen atom or an amino-protecting group;
Is composed of one amino acid residue linked at the C-terminus to the nitrogen atom in formula (II) or two to eight amino acids linked to the nitrogen atom at the C-terminus in formula (II). R ¹ , R ² , and R ³ each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, a carboxyl group, or an alkoxycarbonyl group; R ¹ , R ² ,
And any two of R ³ and R ³ may combine with each other to form a 4- to 8-membered ring; OQ represents a residue of a pharmaceutical compound having a hydroxyl group). 12. The method according to claim 12, wherein R ¹ , R ² and R ³ are hydrogen atoms, and the pharmaceutical compound is 1- [2-amino-6- (4-[(E) -3- [4- (3,5- Difluorophenyl) -1-piperazinyl] -1-propenyl] -1H
12. The compound according to claim 11, which is -pyrazol-1-yl) -4-pyrimidinyl] -3-azetidinol, and wherein Z is -Gly-Gly-Phe-Gly-. 13. The compound according to claim 11, which is used for producing the DDS compound according to any one of claims 1 to 10.