JPWO2022207699A5

JPWO2022207699A5 -

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Publication number: JPWO2022207699A5
Application number: JP2023559766A
Authority: JP
Publication date: 2025-04-02

Description

図１は、実施例３による疎水性相互作用クロマトグラムを表す。FIG. 1 shows a hydrophobic interaction chromatogram according to Example 3. 図２は、実施例３による疎水性相互作用クロマトグラムを表す。FIG. 2 shows the hydrophobic interaction chromatogram according to Example 3. 図３は、実施例４によるコンジュゲートのｉｎｖｉｔｒｏ細胞毒性アッセイを表す。FIG. 3 represents an in vitro cytotoxicity assay of the conjugate according to Example 4. 図３の続き。Continued from Figure 3. 図３の続き。Continued from Figure 3. 図４は、実施例４によるコンジュゲートのｉｎｖｉｔｒｏ細胞毒性アッセイを表す。FIG. 4 represents an in vitro cytotoxicity assay of the conjugate according to Example 4. 図４の続き。Continued from Figure 4. 図４の続き。Continued from Figure 4. 図５は、実施例５によるコンジュゲートのｉｎｖｉｔｒｏ細胞毒性アッセイを表す。FIG. 5 represents an in vitro cytotoxicity assay of the conjugate according to Example 5. 図６は、ラットにおけるｉｎｖｉｖｏ薬物動態プロファイルおよび実施例６による薬物動態パラメータを表す。FIG. 6 represents the in vivo pharmacokinetic profile in rats and the pharmacokinetic parameters according to Example 6. 図７は、ラットにおけるｉｎｖｉｖｏ薬物動態プロファイルおよび実施例６による薬物動態パラメータを表す。FIG. 7 depicts the in vivo pharmacokinetic profile in rats and the pharmacokinetic parameters according to Example 6. 図８は、ラットにおけるｉｎｖｉｖｏ薬物動態プロファイルおよび実施例６による薬物動態パラメータを表す。FIG. 8 represents the in vivo pharmacokinetic profile in rats and the pharmacokinetic parameters according to Example 6. 図９は、ラットにおけるｉｎｖｉｖｏ薬物動態プロファイルおよび実施例６による薬物動態パラメータを表す。FIG. 9 represents the in vivo pharmacokinetic profile in rats and the pharmacokinetic parameters according to Example 6. 図１０は、実施例７による胃癌のマウス異種移植モデルにおける経時的な腫瘍体積を表す。以下に、本願の当初の特許請求の範囲に記載された発明を付記する。（１）以下の式（Ｉ）を有するリガンド－薬物－コンジュゲート化合物（ＬＤＣ） 10 shows the tumor volume over time in a mouse xenograft model of gastric cancer according to Example 7. The invention as originally claimed in the present application is described below. (1) A ligand-drug-conjugate compound (LDC) having the following formula (I):

In the formula,
L is a ligand;
X1 is a connector unit;
Z is an optional spacer;
X2 is a connector unit;
K is any hydrophobic masking material, preferably selected from polysarcosine and polyethylene glycol;
R1 is H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
D is an active agent, preferably selected from the group consisting of a drug, an imaging agent, and a fluorescent agent;
Each R2 is an electron withdrawing group and a C _１1 -C _４4 independently selected from the group consisting of alkyl;
n is 0, 1 or 2;
R4 is H, C _１1 -C _６6 Alkyl and C _２2 -C _６6 alkenyl, wherein said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more groups selected from -O-, -S-, -C(O)-, and -NR''-;
R5 is H, C _１1 -C _６6 Alkyl and C _２2 -C _６6 alkenyl, wherein said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more groups selected from -O-, -S-, -C(O)-, and -NR''-;
T is a sugar cleaving unit or a polypeptide cleaving unit;
Y is O when T is a sugar cleavable unit or NR3 when T is a polypeptide cleavable unit;
R3 is H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
R″ and R′″ are H and C _１1 -C _６6 independently selected from alkyl;
and pharma- ceutically acceptable salts thereof.
(2)
The LDC compound according to (1), wherein L is a ligand selected from the group consisting of a polypeptide, a protein, an antibody and an antibody fragment, and preferably L is an antibody.
(3)
The LDC compound according to (1) or (2), wherein D is selected from the group consisting of drugs, and preferably D is an anti-cancer drug or an immunomodulatory drug.
(4)
X1 and X2 are one or more amino acids, one or more N-substituted amino acids, optionally substituted polyethers, C _１1 -C _１２12 alkylene, arylene having 6 to 10 ring atoms, C _３3 -C _８8 Cycloalkylene, heterocycloalkylene having 5 to 10 ring atoms, heteroarylene having 5 to 10 ring atoms, C _２2 -C _１０10 alkenylene, and any combination thereof;
said alkylene and said alkenylene are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
and the alkylene, the arylene, the cycloalkylene, the heterocycloalkylene, the heteroarylene, and the alkenylene are optionally substituted with one or more substituents selected from the following: halogen, oxo, -OH, -NO _２2 , -C.N., C. _１1 -C _６6 Alkyl, C _３3 -C _６6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C _１1 -C _６6 Alkoxy, C _１1 -C _６6 Haloalkyl, C _１1 -C _６6 haloalkoxy, -(CO)-R', -O-(CO)-R', -(CO)-O-R', -(CO)-NR''R'''', -NR''-(CO)-R', and -NR''R'''';
R', R" and R'" are H and C _１1 -C _６6 The LDC compound according to any one of (1) to (3), wherein each is independently selected from alkyl.
(5)
Z is one or more amino acids, one or more N-substituted amino acids, an optionally substituted polyether, C _１1 -C _１２12 alkylene, arylene having 6 to 10 ring atoms, C _３3 -C _８8 Cycloalkylene, heterocycloalkylene having 5 to 10 ring atoms, heteroarylene having 5 to 10 ring atoms, C _２2 -C _１０10 alkenylene, and any combination thereof;
said alkylene and said alkenylene are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
and the alkylene, the arylene, the cycloalkylene, the heterocycloalkylene, the heteroarylene, and the alkenylene are optionally substituted with one or more substituents selected from the following: halogen, oxo, -OH, -NO _２2 , -C.N., C. _１1 -C _６6 Alkyl, C _３3 -C _６6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C _１1 -C _６6 Alkoxy, C _１1 -C _６6 Haloalkyl, C _１1 -C _６6 haloalkoxy, -(CO)-R', -O-(CO)-R', -(CO)-O-R', -(CO)-NR''R'''', -NR''-(CO)-R', and -NR''R'''';
R', R" and R'" are H and C _１1 -C _６6 The LDC compound according to any one of (1) to (4), wherein each is independently selected from alkyl.
(6)
The LDC compound according to any one of (1) to (5), wherein K is polysarcosine.
(7)
The LDC compound according to any one of (1) to (6), wherein T is a sugar-cleavable unit that is a glucuronide.
(8)
The LDC compound according to any one of (1) to (6), wherein T is a dipeptide, preferably selected from Val-Cit, Val-Ala and Phe-Lys.
(9)
The compound is a compound of formula (VI)

wherein k is an integer from 2 to 50, preferably from 4 to 30; and T is a polypeptide cleavable unit, preferably a dipeptide.
(10)
The compound is of formula (VIII)

In the formula, k is an integer from 2 to 50, preferably from 4 to 30; and T is a sugar cleavable unit, preferably a glucuronide or a galactoside.
(11)
A pharmaceutical composition comprising the LDC compound according to any one of (1) to (10) above and a pharma- ceutically acceptable carrier.
(12)
The LDC compound according to any one of (1) to (10) for use as a drug.
(13)
Intermediate compound of formula (II)

In the formula,
X' is a group capable of reacting with a ligand to form a connector unit;
Z is an optional spacer;
X2 is a connector unit;
K is any hydrophobic masking material, preferably selected from polysarcosine and polyethylene glycol;
R1' is an amino protecting group, H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
D is an active agent, preferably selected from the group consisting of a drug, an imaging agent, and a fluorescent agent;
Each R2 is an electron withdrawing group and a C _１1 -C _４4 independently selected from the group consisting of alkyl;
n is 0, 1 or 2;
R4 is H, C _１1 -C _６6 Alkyl and C _２2 -C _６6 alkenyl, wherein said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more groups selected from -O-, -S-, -C(O)-, and -NR''-;
R5 is H, C _１1 -C _６6 Alkyl and C _２2 -C _６6 alkenyl, wherein said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more groups selected from -O-, -S-, -C(O)-, and -NR''-;
T is a sugar cleaving unit or a polypeptide cleaving unit;
Y' is O when T is a sugar cleavable unit, and NR3' when T is a polypeptide cleavable unit;
R3' is an amino protecting group, H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
R″ and R′″ are H and C _１1 -C _６6 independently selected from alkyl;
and pharma- ceutically acceptable salts thereof.
(14)
K is polysarcosine.
(15)
Intermediate compound of formula (III)

In the formula,
R1' is an amino protecting group, H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
D is an active agent, preferably selected from the group consisting of a drug, an imaging agent, and a fluorescent agent;
Each R2 is an electron withdrawing group and a C _１1 -C _４4 independently selected from the group consisting of alkyl;
n is 0, 1 or 2;
R4 is H, C _１1 -C _６6 Alkyl and C _２2 -C _６6 alkenyl, wherein said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more groups selected from -O-, -S-, -C(O)-, and -NR''-;
R5 is H, C _１1 -C _６6 Alkyl and C _２2 -C _６6 alkenyl, wherein said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more groups selected from -O-, -S-, -C(O)-, and -NR''-;
T is a sugar cleaving unit or a polypeptide cleaving unit;
Y' is O when T is a sugar cleavable unit, and NR3' when T is a polypeptide cleavable unit;
R3' is an amino protecting group, H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
R″ and R′″ are H and C _１1 -C _６6 independently selected from alkyl;
and pharma- ceutically acceptable salts thereof.
(16)
Intermediate compound of formula (IV)

In the formula,
R1' is an amino protecting group, H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
Each R2 is an electron withdrawing group and a C _１1 -C _４4 independently selected from the group consisting of alkyl;
n is 0, 1 or 2;
R4 is H;
R5 is H;
T is a sugar cleavable unit;
Y' is O;
and pharma- ceutically acceptable salts thereof.
(17)
Intermediate compound of formula (IV)

In the formula,
R1' is an amino protecting group, H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
Each R2 is an electron withdrawing group and a C _１1 -C _４4 independently selected from the group consisting of alkyl;
n is 0, 1 or 2;
R4 is H, C _１1 -C _６6 Alkyl and C _２2 -C _６6 alkenyl, wherein said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more groups selected from -O-, -S-, -C(O)-, and -NR''-;
R5 is H, C _１1 -C _６6 Alkyl and C _２2 -C _６6 alkenyl, wherein said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more groups selected from -O-, -S-, -C(O)-, and -NR''-;
Y' is NR3';
T is a polypeptide cleavable unit;
R3' is an amino protecting group, H, C _１1 -C _２４24 Alkyl, C _２2 -C _６6 alkenyl; optionally substituted polyethers, aryl having 6 to 10 ring atoms, C _３3 -C _８8 selected from the group consisting of cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl are optionally interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR"-, -C(O)NR"-, -NR"-C(O)-, -NR"-C(O)-NR""-, -NR"-C(O)-O-, -O-C(O)NR"- and triazole;
R″ and R′″ are H and C _１1 -C _６6 independently selected from alkyl;
and pharma- ceutically acceptable salts thereof.

Claims

Ligand-drug-conjugate compounds (LDCs) having the following formula (I):

In the formula,
L is a ligand selected from the group consisting of proteins, polypeptides, antibodies, and antibody fragments ;
X1 is a connector unit;
Z is an optional spacer;
X2 is a connector unit;
K is any hydrophobic masking material selected from polysarcosine and polyethylene glycol ;
R1 is selected from the group consisting of H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
D is an active agent selected from the group consisting of drugs ;
Each R2 is independently selected from the group consisting of electron withdrawing groups and C ₁ -C ₄ alkyl;
n is 0, 1 or 2;
R4 is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl, said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, and -NR''-;
R5 is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl, said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, and -NR''-;
T is a sugar cleaving unit or a polypeptide cleaving unit;
Y is O when T is a sugar cleavable unit or NR3 when T is a polypeptide cleavable unit;
R3 is selected from the group consisting of H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
R″ and R′″ are independently selected from H and C ₁ -C ₆ alkyl;
and pharma-ceutically acceptable salts thereof.

The LDC compound of claim 1, wherein L is an antibody .

3. The LDC compound of claim 1 or 2, wherein D is an anti-cancer agent or an immunomodulatory agent.

X1 and X2 are independently selected from the group consisting of one or more amino acids, one or more N-substituted amino acids, optionally substituted polyethers, C ₁ -C ₁₂ alkylene, arylene having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkylene, heterocycloalkylene having 5 to 10 ring atoms, heteroarylene having 5 to 10 ring atoms, C ₂ -C ₁₀ alkenylene, and any combination thereof;
said alkylene and said alkenylene may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
and wherein said alkylene, said arylene, said cycloalkylene, said heterocycloalkylene, said heteroarylene, and said alkenylene are optionally substituted with one or more substituents selected from the following: halogen, oxo, -OH, -NO ₂ , -CN, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C ₁ -C ₆ alkoxy, C ₁ -C 6 haloalkyl, C ₁ -C ₆ haloalkoxy, -(CO)-R', -O-(CO)-R', -( _CO )-O-R', -(CO)-NR''R''', -NR''-(CO)-R', and -NR''R'''';
2. The LDC compound of claim 1 , wherein R', R'' and R''' are independently selected from H and C ₁ -C ₆ alkyl.

Z is independently selected from the group consisting of one or more amino acids, one or more N-substituted amino acids, optionally substituted polyethers, C ₁ -C ₁₂ alkylene, arylene having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkylene, heterocycloalkylene having 5 to 10 ring atoms, heteroarylene having 5 to 10 ring atoms, C ₂ -C ₁₀ alkenylene, and any combination thereof;
said alkylene and said alkenylene may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
and wherein said alkylene, said arylene, said cycloalkylene, said heterocycloalkylene, said heteroarylene, and said alkenylene are optionally substituted with one or more substituents selected from the following: halogen, oxo, -OH, -NO ₂ , -CN, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C ₁ -C ₆ alkoxy, C ₁ -C 6 haloalkyl, C ₁ -C ₆ haloalkoxy, -(CO)-R', -O-(CO)-R', -( _CO )-O-R', -(CO)-NR''R''', -NR''-(CO)-R', and -NR''R'''';
2. The LDC compound of claim 1 , wherein R', R'' and R''' are independently selected from H and C ₁ -C ₆ alkyl.

2. The LDC compound of claim 1 , wherein K is polysarcosine.

A pharmaceutical composition comprising the LDC compound of claim 1 and a pharma- ceutically acceptable carrier.

2. The LDC compound of claim 1 for use as a medicament.

Intermediate compound of formula (II)

In the formula,
X1' is a group capable of reacting with a ligand to form a connector unit;
Z is an optional spacer;
X2 is a connector unit;
K is any hydrophobic masking material selected from polysarcosine and polyethylene glycol ;
R1' is selected from the group consisting of an amino protecting group, H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
D is an active agent selected from the group consisting of drugs ;
Each R2 is independently selected from the group consisting of electron withdrawing groups and C ₁ -C ₄ alkyl;
n is 0, 1 or 2;
R4 is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl, said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, and -NR''-;
R5 is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl, said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, and -NR''-;
T is a sugar cleaving unit or a polypeptide cleaving unit;
Y' is O when T is a sugar cleavable unit, and NR3' when T is a polypeptide cleavable unit;
R3' is selected from the group consisting of an amino protecting group, H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
R″ and R′″ are independently selected from H and C ₁ -C ₆ alkyl;
and pharma-ceutically acceptable salts thereof.

The intermediate compound of formula (II) according to claim 9, wherein K is polysarcosine.

Intermediate compound of formula (III)

In the formula,
R1' is selected from the group consisting of an amino protecting group, H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
D is an active agent selected from the group consisting of drugs ;
Each R2 is independently selected from the group consisting of electron withdrawing groups and C ₁ -C ₄ alkyl;
n is 0, 1 or 2;
R4 is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl, said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, and -NR''-;
R5 is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl, said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, and -NR''-;
T is a sugar cleaving unit or a polypeptide cleaving unit;
Y' is O when T is a sugar cleavable unit, and NR3' when T is a polypeptide cleavable unit;
R3' is selected from the group consisting of an amino protecting group, H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
R″ and R′″ are independently selected from H and C ₁ -C ₆ alkyl;
and pharma-ceutically acceptable salts thereof.

Intermediate compound of formula (IV)

In the formula,
R1' is selected from the group consisting of an amino protecting group, H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
Each R2 is independently selected from the group consisting of an electron withdrawing group and a C ₁ -C ₄ alkyl , said electron withdrawing group being selected from the group consisting of a halogen, a haloalkyl, a -CN group, a -SO3H group, a -NO2 group, and a -C(O)R group, where R = H, OH, or alkoxy ;
n is 0, 1 or 2;
R4 is H;
R5 is H;
T is a sugar cleavable unit;
Y' is O;
and pharma-ceutically acceptable salts thereof.

Intermediate compound of formula (IV)

In the formula,
R1' is selected from the group consisting of an amino protecting group, H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
Each R2 is independently selected from the group consisting of electron withdrawing groups and C ₁ -C ₄ alkyl;
n is 0, 1 or 2;
R4 is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl, said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, and -NR''-;
R5 is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₆ alkenyl, said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, and -NR''-;
Y' is NR3';
T is a polypeptide cleavable unit;
R3' is selected from the group consisting of an amino protecting group, H, C ₁ -C ₂₄ alkyl, C ₂ -C ₆ alkenyl; optionally substituted polyether, aryl having 6 to 10 ring atoms, C ₃ -C ₈ cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof;
said alkyl and said alkenyl may be interrupted by one or more heteroatoms or one or more chemical groups selected from -O-, -S-, -C(O)-, -NR''-, -C(O)NR''-, -NR''-C(O)-, -NR''-C(O)-NR'''-, -NR''-C(O)-O-, -O-C(O)NR'' - and triazole;
R″ and R′″ are independently selected from H and C ₁ -C ₆ alkyl;
and pharma-ceutically acceptable salts thereof.