JP5647971B2 - Derivatives of highly active anthracycline antibiotics, production and application of the derivatives - Google Patents

Description

  The present invention relates to a derivative of an anthracycline antibiotic having anticancer activity, a method for producing the derivative, and an application in the production of a therapeutic agent for tumor or cancer.

  Anthracycline antibiotics, especially doxorubicin and daunorubicin, are widely used anticancer drugs. Doxorubicin has a significant therapeutic effect on many solid tumors such as liver cancer, stomach cancer, breast cancer, lung cancer, ovarian cancer and various leukemias. Daunorubicin is also the most effective drug for the treatment of leukemia. However, the side effects such as myelosuppression, cardiotoxicity, and gastrointestinal side effects are conspicuous, so the clinical application of these drugs is limited to some extent. Conventionally, several hundreds of derivatives thereof can be obtained by natural separation or artificial synthesis, and the development of a new generation anticancer agent having high activity and low toxicity is expected. Adriamycin derivative 2-pyrrolindoxorubicin adriamycin (AN-201) synthesized by Attila A. Nagy etc. is 300-1000 times more active than doxorubicin at the cellular level, but the toxicity of AN-201 is too great, Anti-tumor activity was not confirmed at the maximum tolerated dose in a mouse transplant tumor disease model.

  The present invention relates to a derivative of an anthracycline antibiotic having anticancer activity. The derivative of the anthracycline antibiotics according to the present invention has an activity equal to or higher than that of conventional drugs such as adriamycin and daunorubicin at the cellular level, and has resistance in animals that is more desirable than adriamycin and daunorubicin.

その中、
R¹はH、C_1-4炭化水素基又はOC_1-4炭化水素基を示し、
R²はH又はOR⁶を示し、ここで、R⁶はH、C（O）R⁸、ペプチド鎖、C（O）NH₂、C（O）NR⁸R⁹、C（O）Ar-R²⁷、C（O）（C_2-4アルキレン基）COOHまたは式（II）に示される化合物を示し、R⁸、R⁹はそれぞれH、C_1-6炭化水素基を示し、若しくはNR⁸R⁹としてピロリジン-1-イル、ピペリジン-1-イル又はモルホリン-1-イルを示し、Arは芳香環又は複素環式芳香族環を示し、R²⁷は0〜5個の同じ又は異なるF、Cl、NO₂、CN、OH、SH、COOH、NH₂、NR⁸R⁹、C_1-6炭化水素基、OC_1-6炭化水素基、OC（O）C_1-6炭化水素基、C（O）OC_1-6炭化水素基、SC_1-6炭化水素基、S（O）C_1-6炭化水素基又はS（O）₂C_1-6炭化水素基を示し、ペプチド鎖は単一の天然アミノ酸、非天然アミノ酸、又は2〜4個の天然アミノ酸及び/又は非天然アミノ酸からなるペプチド鎖を示し、
WはO又はNHを示し、
R³はH、F、OC_1-4炭化水素基又はC_1-4炭化水素基を示し、
R⁴はH、F、C_1-4炭化水素基又はOR⁷を示し、ここで、R⁷はH、2-ピラニル又はR⁶を示し、
R⁵は式（III）に示される化合物、式（IV）に示される化合物、式（V）に示される化合物又はマレイミド基を示し、
nは1又は2を示し、
XとYはそれぞれC=O又はCR²¹R²²を示し、
QはCH又はNを示し、
R¹⁰、R¹¹、R¹²、R¹³、R¹⁵、R¹⁶はそれぞれH、F、Cl、CN、NO₂、NＨ₂、OH、C（O）OC_1-4炭化水素基、OC（O）C_1-4炭化水素基、OC_1-4炭化水素基、C_1-4炭化水素基、SC_1-6炭化水素基、S（O）C_1-6炭化水素基、S（O）₂C_1-6炭化水素基、（C_0-4アルキレン基）Ar-R²⁷又はNR⁸R⁹を示し、
R²¹、R²²はそれぞれH又はC_1-4炭化水素基を示す。 The present invention provides a compound represented by formula (I) and a salt or solvate thereof.

Among them,
R ¹ represents H, C _1-4 hydrocarbon group or OC _1-4 hydrocarbon group,
R ² represents H or OR ⁶ , wherein R ⁶ is H, C (O) R ⁸ , peptide chain, C (O) NH ₂ , C (O) NR ⁸ R ⁹ , C (O) Ar— R ²⁷ , C (O) (C _2-4 alkylene group) COOH or a compound represented by the formula (II) is shown, R ⁸ and R ⁹ are H, C _1-6 hydrocarbon groups, respectively, or NR ⁸ R ^{9 represents} pyrrolidin-1-yl, piperidin-1-yl or morpholin-1-yl, Ar represents an aromatic ring or a heterocyclic aromatic ring, R ²⁷ represents 0 to 5 same or different F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbon group, OC _1-6 hydrocarbon group, OC (O) C _1-6 hydrocarbon group, C (O) OC _1-6 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon group or S (O) ₂ C _1-6 hydrocarbon group A peptide chain consisting of one natural amino acid, an unnatural amino acid, or 2 to 4 natural amino acids and / or unnatural amino acids,
W represents O or NH;
R ³ represents H, F, OC _1-4 hydrocarbon group or C _1-4 hydrocarbon group,
R ⁴ represents H, F, C _1-4 hydrocarbon group or OR ⁷ , wherein R ⁷ represents H, 2-pyranyl or R ⁶ ;
R ⁵ represents a compound represented by formula (III), a compound represented by formula (IV), a compound represented by formula (V) or a maleimide group,
n represents 1 or 2,
X and Y each represent C = O or CR ²¹ R ²² ;
Q represents CH or N;
R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ are H, F, Cl, CN, NO ₂ , NH ₂ , OH, C (O) OC _1-4 hydrocarbon group, OC (O ) C _1-4 hydrocarbon group, OC _1-4 hydrocarbon group, C _1-4 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon group, S (O) ₂ C _1-6 hydrocarbon group, (C _0-4 alkylene group) Ar—R ²⁷ or NR ⁸ R ⁹ is shown,
R ²¹ and R ²² each represent H or a C _1-4 hydrocarbon group.

The C _1-4 hydrocarbon group described in the present invention may be a linear saturated or unsaturated hydrocarbon group, a branched chain saturated or unsaturated hydrocarbon group, and 0 to 4 identical or different substitutions. By groups such as F, Cl, CN, OH, NO ₂ , COOH, C _1-4 hydrocarbon groups, NHC (O) C _1-6 hydrocarbon groups, NHC (O) Ar—R ²⁷ or NR ⁸ R ⁹ May be substituted. R ⁸ and R ⁹ each represent H, C _1-6 hydrocarbon group, or NR ⁸ R ^{9 represents} pyrrolidin-1-yl, piperidin-1-yl or morpholin-1-yl.

The C _2-4 alkylene group described in the present invention may be a linear saturated or unsaturated alkylene group, may be a branched saturated or unsaturated alkylene group, and 0 to 3 identical or different substituents, such as F, Cl, CN, OH, NO 2, COOH, C 1-4 hydrocarbon group, NHC (O) C _1-6 hydrocarbon group, substituted by NHC (O) Ar-R ²⁷ or NR ⁸ R ⁹ Also good. R ⁸ and R ⁹ each represent H, C _1-6 hydrocarbon group, or NR ⁸ R ^{9 represents} pyrrolidin-1-yl, piperidin-1-yl or morpholin-1-yl.

The C _0-4 alkylene group described in the present invention may be a straight chain saturated or unsaturated alkylene group, a branched chain saturated or unsaturated alkylene group, and 0 to 3 identical or different substituents, such as F, Cl, CN, OH, NO 2, COOH, C 1-4 hydrocarbon group, NHC (O) C _1-6 hydrocarbon group, substituted by NHC (O) Ar-R ²⁷ or NR ⁸ R ⁹ Also good. R ⁸ and R ⁹ each represent H, C _1-6 hydrocarbon group, or NR ⁸ R ^{9 represents} pyrrolidin-1-yl, piperidin-1-yl or morpholin-1-yl.

The C _1-6 hydrocarbon group described in the present invention may be a linear saturated or unsaturated hydrocarbon group, a branched chain saturated or unsaturated hydrocarbon group, and 0 to 4 identical or different substitutions. By groups such as F, Cl, CN, OH, NO ₂ , COOH, C _1-4 hydrocarbon groups, NHC (O) C _1-6 hydrocarbon groups, NHC (O) Ar—R ²⁷ or NR ⁸ R ⁹ May be substituted. R ⁸ and R ⁹ each represent H, C _1-6 hydrocarbon group, or NR ⁸ R ^{9 represents} pyrrolidin-1-yl, piperidin-1-yl or morpholin-1-yl.

  The aromatic ring or heteroaromatic ring described in the present invention represents a benzene ring, naphthalene ring, pyridine ring, pyrrole ring, thiophene ring, furan ring, pyrimidine ring or pyrazine ring.

A compound of formula (I) suitable for the manufacture of a therapeutic agent for tumor or cancer is a compound wherein R ¹ represents H, CH ₃ or OCH ₃ ,
The compound represented by the formula (I) most suitable for the production of a therapeutic agent for tumor or cancer is a compound in which R ¹ represents H or OCH ₃ .

A compound of formula (I) suitable for the manufacture of a therapeutic agent for tumor or cancer is a compound wherein R ² represents H or OR ⁶ . Here, R ⁶ is H, glycyl group, alanyl group, valyl group, leucyl group, isoleucyl group, phenylalani group, seryl group, threonyl group, tyrosyl group, lysyl group, 2-N, N-dimethylaminoacetyl group, 2-N, N-diethylaminoacetyl group, 2-piperidineacetyl group, 2-morpholineacetyl group, 2,2-dimethylglycyl group, 2,2-dimethyl-2-methylaminoacetyl group, 2,2-dimethyl- 2- (N, N-dimethylamino) acetyl group, 2,2-dimethyl-2-ethylaminoacetyl group, 2,2-dimethyl-2- (N, N-diethylamino) acetyl group, 2,2-dimethyl- 2- (N, N-dipropylamino) acetyl group, 2,2-dimethyl-2-piperidineacetyl group, 2,2-dimethyl-2-pyrrolineacetyl group, 2,2-dimethyl-2-morpholineacetyl group, 2,2-dimethyl-2- (N-methyl-N-ethylamino) acetyl group, 2-phenylglycyl group, 2-phenyl-2- Tylaminoacetyl group, 2-phenyl-2- (N, N-dimethylamino) acetyl group, 2-phenyl-2-ethylaminoacetyl group, 2-phenyl-2- (N, N-diethylamino) acetyl, 2- Phenyl-2- (dipropylamino) acetyl group, 2-phenyl-2-piperidineacetyl group, 2-phenyl-2-pyrrolineacetyl group, 2-phenyl-2-morpholineacetyl group, 2-phenyl-2- (N -Methyl-N-ethylamino) acetyl group, acetyl group, propionyl group, butyryl group, pentanoyl group, 3-methylaminopropionyl group, 3-ethylaminopropionyl group, 3-N, N-dimethylaminopropionyl group, 3- N, N-diethylpropionyl group, 3-piperidine propionyl group, 3-pyrrolidine propionyl group, 3-morpholine propionyl group, N-glycylglycyl group, N-alanylglycyl group, N-valylglycyl group, N-seryl group Sil group, N-glycylalanyl group, N-alanylalanyl group, N-valylalanyl group, N-serylalanyl group, N-glycylvalyl group, N-alanylvalyl group, N-valylvalyl group, N-serylvalyl group, succinic acid monoester group, ( 3-nitro-2-carboxyl) benzoic acid ester group, (2-carboxyl) benzoic acid ester group, (2,4-dicarboxyl) benzoic acid ester group, (3,4,5,6-tetrafluoro-2- A carboxyl) benzoate group, a (2-carboxyl-6-fluorine) benzoate group or a (3-fluorine-2-carboxyl) benzoate group;
A compound represented by the formula (I) that is more suitable for producing a therapeutic agent for tumor or cancer is a compound in which R ² represents H or OR ⁶ . Here, R ⁶ is H, glycyl group, alanyl group, valyl group, leucyl group, isoleucyl group, phenylalani group, seryl group, threonyl group, tyrosyl group, lysyl group, 2-N, N-dimethylaminoacetyl group, 2-N, N-diethylaminoacetyl group, 2-piperidineacetyl group, 2-morpholineacetyl group, 2,2-dimethylglycyl group, 2-phenylglycyl group, 3-methylaminopropionyl group, 3-ethylaminopropionyl Group, succinic acid monoester group, (3-nitro-2-carboxyl) benzoic acid ester group, (2-carboxyl) benzoic acid ester group, (2,4-dicarboxyl) benzoic acid ester group, (3,4, 5,6-tetrafluoro-2-carboxyl) benzoic acid ester group, (2-carboxyl-6-fluorine) benzoic acid ester group or (3-fluorine-2-carboxyl) benzoic acid ester.
The compound represented by the formula (I) most suitable for the production of a therapeutic agent for tumor or cancer is a compound in which R ² represents H or OR ⁶ . Here, R ⁶ is H, glycyl group, alanyl group, valyl group, leucyl group, isoleucyl group, phenylalani group, seryl group, threonyl group, tyrosyl group, lysyl group, 2-N, N-dimethylaminoacetyl group, 2-N, N-diethylaminoacetyl group, 2-piperidineacetyl group, 2-morpholineacetyl group, 2,2-dimethylglycyl group, 2-phenylglycyl group, succinic acid monoester group, (3-nitro-2 -Carboxyl) benzoic acid ester group, (2-carboxyl) benzoic acid ester group, (2,4-dicarboxyl) benzoic acid ester group, (3,4,5,6-tetrafluoro-2-carboxyl) benzoic acid ester A group, (2-carboxyl-6-fluorine) benzoic acid ester group or (3-fluoro-2-carboxyl) benzoic acid ester.

A compound of formula (I) suitable for the manufacture of a therapeutic agent for tumor or cancer is a compound wherein W represents O or NH,
The compound represented by the formula (I) most suitable for the production of a therapeutic agent for tumor or cancer is a compound in which W represents O.

A compound of formula (I) suitable for the manufacture of a therapeutic agent for tumor or cancer is a compound wherein R ³ represents H, F, CH ₃ , CH ₂ CH ₃ , OCH ₃ or OCH ₂ CH ₃ ,
A compound represented by formula (I) that is more suitable for the manufacture of a therapeutic agent for tumor or cancer is a compound in which R ³ represents H, CH ₃ or OCH ₃ ,
The compound represented by the formula (I) that is most suitable for the production of a therapeutic agent for tumor or cancer is a compound in which R ³ represents CH ₃ .

Compounds of formula (I) suitable for the manufacture of tumor or cancer therapeutics are those in which R ⁴ is H, F, OH, CH ₃ , OCH ₃ , 2-pyranyl, succinic acid monoester, (3-nitro-2 -Carboxyl) benzoic acid ester group, (2-carboxyl) benzoic acid ester group, (2,4-dicarboxyl) benzoic acid ester group, (3,4,5,6-tetrafluoro-2-carboxyl) benzoic acid ester A group, a (2-carboxyl-6-fluorine) benzoic acid ester group or a (3-fluorine-2-carboxyl) benzoic acid ester,
A compound represented by formula (I) that is more suitable for producing a therapeutic agent for tumor or cancer is a compound in which R ⁴ represents OH, OCH ₃ , 2-pyranyl or succinic acid monoester,
The compounds of formula (I) that are most suitable for the manufacture of tumor or cancer therapeutics are those in which R ⁴ represents OH, 2-pyranyl or succinic acid monoester.

Compounds of formula (I) suitable for the manufacture of a therapeutic agent for tumors or cancers are those in which R ⁵ is pyrrol-1-yl, succinimide group, glutarimide group, butyrolactam-1-yl, valerolactam-1-yl, 3 -Methyl-pyrrol-1-yl, 3-methoxy-pyrrol-1-yl, 3-methyl-succinimide group, 3-methoxy-succinimide group, 3-methyl-glutarimide group, 3-methoxy-glutarimide group, 3 -Methyl-butyrolactam-1-yl, 3-methoxybutyrolactam-1-yl, 3-methyl-valerolactam-1-yl, 3-methoxy-valerolactam-1-yl, 4-methyl-valerolactam-1 -Yl, 4-methoxy-valerolactam-1-yl, benzosuccinimido-1-yl, pyrrolosuccinimido-1-yl
The compound represented by formula (I) most suitable for the manufacture of a therapeutic agent for tumor or cancer is that R ⁵ is pyrrol-1-yl, succinimide group, glutarimide group, butyrolactam-1-yl, valerolactam-1-yl. It is a compound to show.

Although not described in the specification, a compound having a chiral center according to the present invention, which can be confirmed from the structural formula, or described as R-type or S-type, is R-type, S-type or a mixture thereof. Also good .

Note that prodrugs, salts or active metabolites of the compounds disclosed in the specification are also included in the scope of the present invention.

式（VII）に示される化合物におけるR¹、R³、R⁴及びWが示すグループは、式（I）に示される化合物におけるR¹、R³、R⁴及びWが示すグループと同一であり、R²⁰はH又はOHを示し、
式（VI）に示される化合物におけるR¹、R³、R⁴、R⁵及びWが示すグループは、式（I）に示される化合物におけるR¹、R³、R⁴、R⁵及びWが示すグループと同一であり、R²⁰はH又はOHを示し、
式（VIII）に示される化合物におけるR¹⁶は、式（V）に示される化合物におけるR¹⁶が示すグループと同一であり、R²¹及びR²²はそれぞれH又はC_1-4炭化水素基を示す。 The present invention discloses a process for preparing the compound of formula (VI), an important intermediate of the compound of formula (I). As the first manufacturing method,

The group represented by R ¹ , R ³ , R ⁴ and W in the compound represented by formula (VII) is the same as the group represented by R ¹ , R ³ , R ⁴ and W in the compound represented by formula (I) , R ²⁰ represents H or OH,
Group represented by ^{R 1, R 3, R 4} , R 5 and W in a compound represented by formula (VI) is ^{R 1, R 3, R 4} , R 5 and W in a compound represented by formula (I) Identical to the group shown, R ²⁰ represents H or OH,
R ¹⁶ in the compound represented by the formula (VIII) is the same as the group represented by R ¹⁶ in the compound represented by the formula (V), and R ²¹ and R ²² each represent H or a C _1-4 hydrocarbon group. .

According to the present invention, the salt of the compound represented by the formula (VII) is obtained by reacting the compound represented by the formula (VII) with hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, methylsulfonic acid, benzenesulfonic acid or p-toluenesulfone. A salt formed with one or a mixture of acids .

  The compound represented by the formula (VII) or a salt thereof is reacted with the compound represented by the above formula (VIII) in the presence of an acidic and / or alkaline reagent to obtain the compound represented by the formula (VI). Among them, acidic reagents are hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, methylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, lactic acid or One or a mixture of one or more selected from malic acid. The amount of the acidic reagent used is 0.05 to 500 times (molar amount) of the compound represented by formula (VII), preferably 0.2 to 50 times (molar amount) of the compound represented by formula (VII), More desirably, it is 0.7 to 5 times (molar amount) of the compound represented by the formula (VII). The alkaline reagent is potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, phosphorous Dipotassium hydrogenate, sodium lactate, potassium lactate, sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, sodium malate, potassium malate, sodium propionate, potassium propionate, sodium butyrate, potassium butyrate, sodium oxalate , Potassium oxalate, sodium pentanoate, potassium pentanoate, sodium glutarate, potassium glutarate, triethylamine, trimethylamine, diisopropylethylamine, 4-dimethylaminopyridy A 4 (pyrrolidin-1-yl) piperidine, piperidine, or one or a mixture of one or more kinds selected from N- methylmorpholine. The amount of the alkaline reagent used is 0.05 to 500 times (molar amount) of the compound represented by formula (VII), desirably 0.2 to 50 times (molar amount) of the compound represented by formula (VII), and more. Desirably, it is 0.7 to 5 times (molar amount) of the compound represented by the formula (VII). The temperature of the reaction is −20 to 150 ° C., desirably −10 to 100 ° C., more desirably −10 to 80 ° C. Reaction is dichloromethane, trichloromethane, N, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, ethanol, methanol, isopropanol, tetrahydrofuran, ethyl acetate, methyl acetate, methyl propionate, ethyl propionate, ethylene Glycol diethyl ether, ethylene glycol monoethyl ether, N, N-diethylformamide, 1,2-dichloroethane, acetonitrile, water or a mixture of one or more solvents of the compound represented by formula (VIII). If necessary, an organic base such as triethylamine, trimethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 4 (pyrrolidin-1-yl) piperidine, piperidine or N-methylmorpholine may be used as a catalyst. The amount of the organic base used as the catalyst is 0.01 to 2 times the molar amount of the compound shown in (VII), preferably 0.05 to 0.2 times the molar amount of the compound shown in (VII). The charged molar ratio of the compound represented by the formula (VII) or a salt thereof and the compound represented by the formula (VIII) is 1: 0.1 to 1: 10000, desirably 1: 0.5 to 1: 1000, and more desirably. Is 1: 1 to 1: 500.

その中、
式（IX）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³及びnが示すグループは、式（III）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³及びnが示すグループと同一であり、
式（X）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³及びnが示すグループは、式（III）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³及びnが示すグループと同一であり、
式（X）に示される化合物におけるR¹、R³、R⁴及びWが示すグループは、式（VII）に示される化合物におけるR¹、R³、R⁴及びWが示すグループと同一あり、
R²⁰はH又はOHを示す。 As the second production method of the compound represented by the formula (VI) according to the present invention,

Among them,
The group represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and n in the compound represented by formula (IX) is the group represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and n in the compound represented by formula (III). Is identical to the group shown,
Group represented by ^{R 10, R 11, R 12} , R 13 and n in a compound represented by formula (X) is ^{R 10, R 11, R 12} , R 13 and n in a compound represented by formula (III) Is identical to the group shown,
The group represented by R ¹ , R ³ , R ⁴ and W in the compound represented by the formula (X) is the same as the group represented by R ¹ , R ³ , R ⁴ and W in the compound represented by the formula (VII),
R ²⁰ represents H or OH.

  The compound represented by the formula (VII) or a salt thereof is dichloromethane, trichloromethane, carbon tetrachloride, ethyl acetate, methyl acetate, methyl propionate, ethyl propionate, 1,2-dichloroethane, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, One or a mixture of ethylene glycol diethyl ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide, acetonitrile or water reacts with the compound represented by formula (IX) to give the formula ( The compound shown in X) is obtained. During the reaction, one or a mixture of pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine may or may not be added as a catalyst. Good. The amount of the catalyst used is 0.01 to 10 times the molar amount of the compound represented by the formula (VII), desirably 0.02 to 5 times the molar amount of the compound represented by the formula (VII), more desirably It is 0.05 to 1 times the molar amount of the compound shown in (VII). During the reaction, triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methylpyridine, N-ethylpyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine, 4- (pyrrolidin-1-yl) -Pyridine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydroxide, or a mixture of one or more potassium hydroxides may be added as a deacid reagent. The amount of the acid binder used is 0.4 to 20 times the molar amount of the compound represented by the formula (VII), desirably 0.8 to 10 times the molar amount of the compound represented by the formula (VII), and more desirably. Is 1 to 5 times the molar amount of the compound represented by formula (VII). The reaction temperature is -20 to 100 ° C, preferably -10 to 80 ° C, more preferably -5 to 80 ° C. The charged molar ratio of the compound represented by the formula (IX) or a salt thereof and the compound represented by the formula (VII) is 1: 0.1 to 1:10, desirably 1: 0.5 to 1: 5, and more desirably. Is 1: 0.8 to 1: 3.

  The compound represented by the formula (X) reacts under the action of a dehydrating agent to obtain the compound represented by the formula (VI). Here, the dehydrating agent is DCC (dicyclohexylcarbodiimide), EDC HCL (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), CDI (N, N′-carbonyldiimidazole) or DIC (N, N′-diisopropylcarbodiimide). The amount of the dehydrating agent used is 0.1 to 10 times the molar amount of the compound represented by formula (X), desirably 0.5 to 5 times the molar amount of the compound represented by formula (X), and more desirably It is 1 to 3 times the molar amount of the compound represented by (X). The reaction temperature is −10 to 120 ° C., desirably 0 to 100 ° C., more desirably 0 to 80 ° C. Reaction is dichloromethane, trichloromethane, ethyl acetate, methyl acetate methyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide or It is carried out in one or more mixed liquids of acetonitrile.

その中、
式（XI）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³、R²¹、R²²及びnが示すグループは、式（III）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³、R²¹、R²²及びnが示すグループと同一であり、
UはCl、Br、I、OTs（p-トルエンスルホン酸エステル）又はOMs（メタンスルホン酸エステル）を示し、
TはF、Cl、Br、OSu、OBt又はOAtを示し
式（XIII）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³、R²¹、R²²、n及びUが示すグループは、式（XI）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³、R²¹、R²²、n及びUが示すグループと同一であり、
式（XIII）に示される化合物におけるR¹、R³、R⁴、R²⁰及びWが示すグループは、式（VII）に示される化合物におけるR¹、R³、R⁴、R²⁰及びWが示すグループと同一である。 As a third production method of the compound represented by the formula (VI) according to the present invention,

Among them,
Group represented by ^{R 10, R 11, R 12} , R 13, R 21, R 22 and n in a compound represented by formula (XI), R ¹⁰ in the compound represented by formula ^{(III), R 11, R} 12 , R ¹³ , R ²¹ , R ²² and n are the same as the group represented by
U represents Cl, Br, I, OTs (p-toluenesulfonic acid ester) or OMs (methanesulfonic acid ester),
T represents F, Cl, Br, OSu, OBt or OAt, and the group represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , n and U in the compound represented by the formula (XIII) is: The same as the group represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , n and U in the compound represented by the formula (XI);
The group represented by R ¹ , R ³ , R ⁴ , R ²⁰ and W in the compound represented by the formula (XIII) is the group represented by R ¹ , R ³ , R ⁴ , R ²⁰ and W in the compound represented by the formula (VII). It is the same as the group shown.

  A compound represented by the formula (VII) or a salt thereof is reacted with a compound represented by the formula (XI) under the action of an alkali to obtain a compound represented by the formula (XIII). Here, the alkali is triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine, 4- (pyrrolidin-1-yl) -pyridine, N-methylmorpholine, N-methylpiperidine, N -One or a mixture of one or more selected from ethylpiperidine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. The amount of alkali used is 0.5 to 10 times the molar amount of the compound represented by formula (VII) or a salt thereof, and preferably 0.8 to 7 times the molar amount of the compound represented by formula (VII) or a salt thereof. More desirably, it is 1 to 5 times the molar amount of the compound represented by the formula (VII) or a salt thereof. Reaction is dichloromethane, trichloromethane, 1,2-dichloroethane, acetone, ethyl acetate, isopropanol, methyl acetate, propyl acetate, methyl propionate, ethyl propionate, acetonitrile, ethanol, N, N-dimethylformamide, N, N- The reaction is carried out in one or a mixture of one or more of diethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol, ethanol or propanol. The reaction temperature is -20 to 120 ° C, desirably -10 to 100 ° C, more desirably 0 to 80 ° C. The charged molar ratio of the compound represented by the formula (VII) or a salt thereof and the compound represented by the formula (XI) is 1: 0.2 to 1:10, desirably 1: 0.5 to 1: 5, and more desirably. Is 1: 0.8 to 1: 3.

  The compound represented by the formula (XIII) reacts under the action of an alkaline reagent to obtain the compound represented by the formula (VI). The alkaline reagent is triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine, 4- (pyrrolidin-1-yl) -pyridine, N-methylmorpholine, N-methylpiperidine, N-ethyl Piperidine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium oxide, potassium oxide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hexamethyl One or a mixture of one or more selected from disilazide. The amount of alkali used is 0.5 to 3 times the molar amount of the compound represented by formula (XIII) or a salt thereof, and preferably 0.8 to 2 times the molar amount of the compound represented by formula (XIII) or a salt thereof. More desirably, it is 1 to 1.5 times the molar amount of the compound represented by the formula (XIII) or a salt thereof. Reaction is dichloromethane, trichloromethane, 1,2-dichloroethane, acetone, ethyl acetate, isopropanol, methyl acetate, propyl acetate, methyl propionate, ethyl propionate, acetonitrile, N, N-dimethylformamide, N, N-diethylformamide , Dimethyl sulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, or ethylene glycol diethyl ether. The reaction temperature is -20 to 120 ° C, desirably -10 to 100 ° C, more desirably 0 to 80 ° C.

そのうち、式（XIV）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³、R²¹、R²²及びnが示すグループは、式（III）に示される化合物におけるR¹⁰、R¹¹、R¹²、R¹³、R²¹、R²²及びnが示すグループと同一である。 As a fourth production method of the compound represented by the formula (VI) according to the present invention,

Among them, the groups represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² and n in the compound represented by the formula (XIV) are R ¹⁰ , R ¹¹ , It is the same as the group represented by R ¹² , R ¹³ , R ²¹ , R ²² and n.

  The compound represented by the formula (XIV) reacts with the compound represented by the formula (VII) or a salt thereof under the action of an alkaline reagent and / or an acidic reagent to obtain the compound represented by the formula (VI). Here, the alkaline reagent is selected from triethylamine, trimethylamine, pyridine, N-methylmorpholine, N-methylpiperidine, N-ethylpiperidine, diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate. Or a mixture of more than one. The amount of alkali used is 0.5 to 10 times the molar amount of the compound represented by formula (VII) or a salt thereof, and preferably 0.8 to 5 times the molar amount of the compound represented by formula (VII) or a salt thereof. More desirably, it is 1 to 3 times the molar amount of the compound represented by the formula (VII) or a salt thereof. Here, the acidic reagent is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, methylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, lactic acid. Alternatively, it is one or a mixture of one or more selected from malic acid. The amount of the acidic reagent used is 0.05 to 500 times (molar amount) of the compound represented by formula (VII), preferably 0.2 to 50 times (molar amount) of the compound represented by formula (VII), and more desirably. Is 0.7 to 5 times (molar amount) of the compound represented by formula (VII). Reaction is dichloromethane, trichloromethane, acetone, acetonitrile, ethyl acetate, methanol, ethanol, propanol, isopropanol, ethylene glycol, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, methyl acetate , Propyl acetate, methyl propionate, ethyl propionate, N, N-dimethylformamide, N, N-diethylformamide, or dimethyl sulfoxide. The reaction temperature is -20 to 100 ° C, preferably -10 to 80 ° C, more preferably 0 to 50 ° C.

その中、
式（XV）におけるR¹⁵とQが示すグループは、式（IV）におけるR¹⁵和Qが示すグループと同一である。式（XVI）におけるR¹⁵とQが示すグループは、式（IV）におけるR¹⁵和Qが示すグループと同一であり、式（XVI）における中R¹、R³、R⁴、R²⁰及びWが示すグループは、式（VII）に示される化合物におけるR¹、R³、R⁴、R²⁰及びWが示すグループと同じである。式（XVII）におけるR¹⁵とQが示すグループは、式（IV）におけるR¹⁵とQが示すグループと同一であり、式（XVII）におけるR¹、R³、R⁴、R²⁰及びWが示すグループは、式（VII）に示される化合物におけるR¹、R³、R⁴、R²⁰及びWが示すグループと同一である。 As a fifth production method of the compound represented by the formula (VI) according to the present invention,

Among them,
The group represented by R ¹⁵ and Q in Formula (XV) is the same as the group represented by R ¹⁵ sum Q in Formula (IV). The group represented by R ¹⁵ and Q in formula (XVI) is the same as the group represented by R ¹⁵ sum Q in formula (IV), and R ¹ , R ³ , R ⁴ , R ²⁰ and W in formula (XVI) Is the same as the group represented by R ¹ , R ³ , R ⁴ , R ²⁰ and W in the compound represented by formula (VII). Group indicated by R ¹⁵ and Q in the formula (XVII) are the same as group indicated by R ¹⁵ and Q in formula ^{(IV), R 1, R} 3 in the formula ^{(XVII), R 4, R} 20 and W are The group shown is the same as the group represented by R ¹ , R ³ , R ⁴ , R ²⁰ and W in the compound represented by formula (VII).

  A compound represented by the formula (VII) or a salt thereof is dichloromethane, trichloromethane, carbon tetrachloride, ethyl acetate, methyl acetate, methyl propionate, ethyl propionate, 1,2-dichloroethane, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, In one or a mixture of one or more of ethylene glycol diethyl ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide, acetonitrile or water, the compound represented by the formula (XV) A compound represented by XVI) or (XVII) is obtained. During the reaction, one or a mixture of pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine may or may not be added as a catalyst. The amount of the catalyst used is 0.01 to 10 times the molar amount of the compound represented by the formula (VII), desirably 0.02 to 5 times the molar amount of the compound represented by the formula (VII), more desirably the formula (VII). VII) 0.05-1 times the molar amount of the compound shown. During the reaction, triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-ethylpiperidine, 4-dimethylaminopyridine, 4-diethylaminopyridine, 4- (pyrrolidin-1-yl) -pyridine One or more kinds of potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide may be added as an acid binder. The amount of the acid binder used is 0.4 to 20 times the molar amount of the compound represented by the formula (VII), desirably 0.8 to 10 times the molar amount of the compound represented by the formula (VII), more desirably 1 to 5 times the molar amount of the compound represented by formula (VII). The reaction temperature is -20 to 100 ° C, preferably -10 to 80 ° C, more preferably 0 to 80 ° C. The charged molar ratio of the compound represented by the formula (VII) or a salt thereof and the compound represented by the formula (XV) is 1: 0.2 to 1:10, preferably 1: 0.5 to 1: 5, more preferably Is 1: 0.8 to 1: 3.

  A compound represented by formula (XVI) or formula (XVII) reacts under the action of a dehydrating agent to obtain a compound represented by formula (VI). Among them, the dehydrating agent is DCC (dicyclohexylcarbodiimide), EDC HCL (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), CDI (N, N′-carbonyldiimidazole) or DIC (N, N′-diisopropylcarbodiimide). The amount of the dehydrating agent used is 0.1 to 10 times the molar amount of the compound represented by the formula (XVI) or the formula (XVII), preferably 0.5% of the molar amount of the compound represented by the formula (XVI) or the formula (XVII). -5 times, more preferably 1-3 times the molar amount of the compound represented by formula (XVI) or formula (XVII). The reaction temperature is −10 to 120 ° C., desirably 0 to 100 ° C., more desirably 20 to 100 ° C. Reaction is dichloromethane, trichloromethane, ethyl acetate, methyl acetate methyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide or It is carried out in one or more mixed liquids of acetonitrile. During the reaction, one or a mixture of pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine may be added as a catalyst. The amount of the catalyst used is 0.01 to 1 times the molar amount of the compound represented by formula (XVI) or formula (XVII), preferably 0.02 to the molar amount of the compound represented by formula (XVI) or formula (XVII). 0.8 times, more desirably 0.03 to 0.5 times the molar amount of the compound represented by formula (XVI) or formula (XVII).

そのうち、式（XX）に示される化合物におけるR¹⁵、X、YとQが示すグループは、式（IV）に示される化合物におけるR¹⁵、X、YとQが示すグループと同一であり、式（XX）に示される化合物におけるUがCl、Br、OMs （メタンスルホン酸エステル）又はOTs（p-トルエンスルホン酸エステル）を示す。 As a sixth production method of the compound represented by the formula (VI) according to the present invention,

Among them, the group represented by R ¹⁵ , X, Y and Q in the compound represented by the formula (XX) is the same as the group represented by R ¹⁵ , X, Y and Q in the compound represented by the formula (IV), U in the compound represented by (XX) represents Cl, Br, OMs (methanesulfonic acid ester) or OTs (p-toluenesulfonic acid ester).

  The compound represented by the formula (VII) or a salt thereof is dichloromethane, trichloromethane, carbon tetrachloride, ethyl acetate, methyl acetate, methyl propionate, ethyl propionate, 1,2-dichloroethane, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, A compound represented by the formula (XX) under the action of an alkali in one or a mixture of ethylene glycol diethyl ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide, acetonitrile or water. To give a compound of formula (VI). During the reaction, one or a mixture of pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine may or may not be added as a catalyst. The amount of the catalyst used is 0.01 to 10 times the molar amount of the compound represented by the formula (VII), preferably 0.02 to 5 times the molar amount of the compound represented by the formula (VII), more preferably the formula (VII). VII) 0.05-1 times the molar amount of the compound shown. Alkali added during the reaction is triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-ethylpiperidine, 4-dimethylaminopyridine, 4-diethylaminopyridine, 4- (pyrrolidine-1- Yl) -pyridine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydroxide, or a mixture of one or more potassium hydroxides, including but not limited to. The amount of alkali used during the reaction is 0.4 to 20 times the molar amount of the compound represented by formula (VII), preferably 0.8 to 10 times the molar amount of the compound represented by formula (VII), and more Desirably, it is 1 to 5 times the molar amount of the compound represented by the formula (VII). The reaction temperature is -20 to 100 ° C, preferably -10 to 80 ° C, more preferably 0 to 80 ° C. The charged molar ratio of the compound represented by the formula (VII) or a salt thereof and the compound represented by the formula (XX) is 1: 0.2 to 1:10, desirably 1: 0.5 to 1: 5, and more desirably. Is 1: 0.8 to 1: 3.

As the first production method of the compound represented by the formula (I) according to the present invention,
In the case where R ²⁰ represents OH, the compound represented by formula (VI) is selected from R ⁸ COOH, peptide chain, HOOC-Ar-R ²⁷ , compound represented by formula (IX), compound represented by formula (XV) or Reaction with a compound represented by formula (XXI) yields a compound represented by formula (I).

Among them,
R ⁸ in R ⁸ COOH represents H or C _1-6 hydrocarbon group,
R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each represent H or C _1-6 hydrocarbon group,
Ar represents an aromatic ring or a heterocyclic aromatic ring,
R ²⁷ is the same or different from 0 to 5 F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbon group, OC _1-6 hydrocarbon group, OC (O) C _1-6 hydrocarbon group, C (O) OC _1-6 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon group or S (O) ₂ C _{1 -6 represents a} hydrocarbon group. The peptide chain has a free carboxyl group, has 0 to 2 identical or different C _1-6 hydrocarbon groups at the N-terminus, or an amino group selected from Fmoc, Boc, CBZ, Tr or Alloc. Has a protecting group.

During the reaction, a condensing agent selected from one or a mixture of DCC, EDC HCL, CDI or DIC may be added. The amount of the condensing agent used is 0.1 to 10 times the molar amount of the compound represented by the formula (VI), desirably 0.5 to 5 times the molar amount of the compound represented by the formula (VI), more desirably the formula It is 1 to 3 times the molar amount of the compound shown in (VI). The reaction temperature is −10 to 120 ° C., desirably 0 to 100 ° C., more desirably 20 to 100 ° C. Reaction is dichloromethane, trichloromethane, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl It is carried out in one kind or a mixture of one or more kinds of sulfoxide or acetonitrile. During the reaction, one or a mixture of pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine may or may not be added as a catalyst. The amount of the catalyst used is 0.01 to 10 times the molar amount of the compound represented by formula (VI), preferably 0.02 to 5 times the molar amount of the compound represented by formula (VI), more preferably It is 0.05-1 times the molar amount of the compound shown in (VI). The charge molar ratio of the compound represented by the formula (VI) and R ⁸ COOH, peptide chain, HOOC-Ar-R ²⁷ or the compound represented by the formula (XXI) is 1: 0.2 to 1:10, preferably 1 : 0.5-1: 7, more preferably 1: 0.8-1: 5. If necessary, alkali may be added as an acid binder. Alkali added during the reaction is triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-ethylpiperidine, 4-dimethylaminopyridine, 4-diethylaminopyridine, 4- (pyrrolidine-1- Yl) -pyridine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydroxide, or a mixture of one or more potassium hydroxides, including but not limited to. The amount of alkali used during the reaction is 0.4 to 20 times the molar amount of the compound represented by formula (VI), preferably 0.8 to 10 times the molar amount of the compound represented by formula (VI), More desirably, it is 1 to 5 times the molar amount of the compound represented by the formula (VI).

The compound represented by formula (VI) is reacted with a peptide chain having a protecting group at the N-terminus to obtain a product, and a desired compound is obtained through a conventional deprotection reaction used by those skilled in the art. That is, Fmoc can be removed by NH ₃ , aminoethanol, dimethylamine, diethylamine, pyridine, piperazine or DBU, and Boc or Tr is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, trifluoroacetic acid, methylsulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid or HCl.

As the second production method of the compound represented by the formula (I) according to the present invention,
When R ²⁰ represents OH, the compound represented by formula (VI) is reacted with R ⁸ NCO to obtain the compound represented by formula (I). R ⁸ represents a C _1-6 hydrocarbon group. The charging ratio of the compound represented by the formula (VI) and R ⁸ NCO is 1: 0.5 to 1: 5, preferably 1: 0.7 to 1: 2, more preferably 1: 0.8 to 1: 1.5. is there. During the reaction, triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-ethylpiperidine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine Or a mixture of one or more tertiary amines such as The addition amount of the tertiary amine is 0.5 to 10 times the molar amount of the compound represented by the formula (VI), desirably 0.5 to 7 times the molar amount of the compound represented by the formula (VI), and more desirably Is 0.5 to 3 times the molar amount of the compound represented by formula (VI). During the reaction, one or a mixture of one or more of 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine may be added as a catalyst. The addition amount of the catalyst is 0.01 to 1 times the molar amount of the compound represented by the formula (VI), desirably 0.02 to 0.8 times the molar amount of the compound represented by the formula (VI), more desirably the formula (VI It is 0.05 to 0.3 times the molar amount of the compound shown in VI). The reaction temperature is −10 to 120 ° C., desirably 0 to 100 ° C., more desirably 0 to 100 ° C. Reaction is dichloromethane, trichloromethane, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl It is carried out in one or a mixture of one or more of sulfoxide or acetonitrile.

As a third production method of the compound represented by the formula (I) according to the present invention,
In the case where R ²⁰ represents OH, the compound represented by the formula (VI) is reacted with phosgene, diphosgene or triphosgene, and further R ⁸ NCO is added to react to obtain the compound represented by the formula (I). The charged molar ratio of the compound represented by the formula (VI) and phosgene, diphosgene or triphosgene is 1: 0.5 to 1: 5, preferably 1: 0.7 to 1: 3, more preferably 1: 0.9 to 1. : 2 The charged molar ratio of the compound represented by the formula (VI) and HNR ⁸ R ⁹ is 1: 0.5 to 1: 5, preferably 1: 0.7 to 1: 3, more preferably 1: 0.9 to 1: 2.

During the reaction, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, tertiary amines such as triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N One or a mixture of one or more of -ethylpiperidine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine may be added . The addition amount of the acid binder is 1 to 20 times the molar amount of the compound represented by the formula (VI), desirably 1.5 to 15 times the molar amount of the compound represented by the formula (VI), more desirably 2 to 10 times the molar amount of the compound represented by formula (VI). During the reaction, one or a mixture of one or more of 4-dimethylaminopyridine, 4-diethylaminopyridine or 4- (pyrrolidin-1-yl) -pyridine may be added as a catalyst. The addition amount of the catalyst is 0.01 to 1 times the molar amount of the compound represented by the formula (VI), desirably 0.02 to 0.8 times the molar amount of the compound represented by the formula (VI), more desirably the formula (VI It is 0.05 to 0.3 times the molar amount of the compound shown in VI). The reaction temperature is −100 to 120 ° C., desirably −78 to 100 ° C., more desirably −78 to 80 ° C. Reaction is dichloromethane, trichloromethane, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl It is carried out in one or a mixture of one or more of sulfoxide or acetonitrile.

  The compound represented by the formula (I) is used for the manufacture of a therapeutic agent for cancer or tumor, among which the intestine cancer, liver cancer, stomach cancer, breast cancer, lung cancer, kidney cancer, cervical cancer, pancreatic cancer , Ovarian cancer, prostate cancer, glioma, lymphoma, skin cancer, pigmented tumor, thyroid cancer, multiple myeloma or leukemia.

  The therapeutic agent for cancer or tumor produced from the compound represented by the formula (I) includes other suitable anticancer agents such as paclitaxel anticancer agents, camptothecin anticancer agents, vinblastine anticancer agents, cyclophosphamide, 5-fluorouracil, It can be used in combination with one or more of thalidomide, cisplatin, Revlimid, tarceva, Irresa, Gleveec, etc. In the case of combination, they may be administered sequentially or simultaneously.

  The dosage form of the therapeutic agent for cancer or tumor produced from the compound represented by formula (I) is determined by the mode of administration of the drug, for example, gastrointestinal tract administration, intravenous infusion, intraperitoneal administration, intradermal administration, intramuscular administration There are administration modes such as intranasal administration or local administration. In addition to the inclusion of the compound of formula (I), the selected dosage form contains suitable drug carriers necessary for the preparation of the dosage form, such as fillers, solvents, diluents, colorants and / or binders, etc. Can be contained.

A preferable dosage form of a therapeutic agent for cancer or tumor produced from the compound represented by formula (I) is an injectable dosage form, and a powder needle, a lyophilized powder needle, a water needle, an emulsion or a suspension is used as the dosage form. Including, but not limited to.
Abbreviations:
Su: Succinimide group
Bt: Benzotriazol-1-yl
At: 7-azabenzotriazol-1-yl
Fmoc: Fluorenylmethoxycarbonyl group
Boc: tert-butoxycarbonyl group
CBZ: Benzoyloxycarbonyl group
Tr: Trimethylphenyl
Alloc: Allyloxy formyl group
DBU: 1,8-diazabicyclo [5,4,0] undec-7-ene

[Example 1]
3'-pyrrole adriamycin
Add 3.076 g of adriamycin (Doxorubicin) hydrochloride to a 1 L three-necked flask, and add 300 ml of distilled water, 300 ml of 1,2-dichloroethane, 30 ml of 2,5-dimethoxytetrahydrofuran and 6 ml of glacial acetic acid. The reaction is completed by refluxing for 45 minutes under the protection of argon gas. The reaction solution is cooled to room temperature, placed in 200 ml of ice water, and allowed to stand and separate. The organic phase is washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered and spin-dried,
In an ice bath, add 100 ml of 5% sodium bicarbonate to the aqueous phase with stirring, extract with chloroform (50 ml × 3), collect the chloroform layer, wash the chloroform layer once with 100 ml of saturated brine, filter, The solvent is removed by rotation, and the resulting crude product and the crude product obtained above are combined, purified by column chromatography, and eluted with chloroform and methanol = 35: 1 to give 2.95 g of product. MS: 592 (M-1)

  The compounds shown in Examples 2 to 6 are synthesized by the same method.

[Example 2]
3′-pyrrole-5-iminodaunomycin, MS: 576 (M−1).

[Example 3]
3'-pyrrole-idarubicin, MS: 547 (M-1).

[Example 4]
3'-pyrrole-esorubicin, MS: 577 (M-1).

[Example 5]
3'-pyrrole doxorubicin, MS: 577 (M-1).

[Example 6]
3'-Pyrrol-4 '-(pyran-2-yl) adriamycin, MS: 677 (M-1).

[Example 7]
3'-succinimide adriamycin
Add 100 mg of adriamycin hydrochloride to a 50 ml single-necked round bottom flask, dissolve in 3 ml of DMF, add 63 μl DIEA (diisopropylethylamine) and 2 mg of DMAP (4-dimethylaminopyridine) and stir for 10 minutes, add 21 mg of succinic anhydride, Allow to stir at room temperature for 1 hour under the protection of argon gas. The reaction solution is spin-dried, and 20 ml of distilled water and 10 ml of chloroform are added to the remaining material, and an extraction filter and a filter cake are obtained. The obtained filter cake is dried, 18 mg is taken into a 50 ml one-necked flask, 5 ml of dichloromethane (dry molecular sieve) and 12 μl of triethylamine (dry molecular sieve) are added, and 69 ml of cyanuric chloride is further added, and the mixture is stirred at room temperature with stirring. . 20 ml of dichloromethane is added to the reaction solution, washed once with 20 ml of water, all the organic phases obtained are washed once with 20 ml of saline, and the solvent is rotated and removed to obtain a crude product. The thin layer is purified by chromatography and developed with chloroform, methanol = 22: 1 to give the desired compound. MS: 624 (M-1).

  The compounds shown in Examples 8 to 11 are synthesized by the same method.

[Example 8]
3′-glutarimidoadriamycin, MS: 1296 (2M + H ₂ O).

[Example 9]
3'-cis-butenediimide adriamycin, MS: 623 (M).

[Example 10]
3 '-(pyrrolo- (2,3) succinimide) adriamycin, MS: 722 (M + EtOH).

[Example 11]
3 '-(benzo- (2,3) succinimide) adriamycin, MS: 1345 (2M).

[Example 12]
3'-Butylactam Adriamycin Take 10 mg of Adriamycin hydrochloride and dissolve in 5 ml of DMF (anhydrous), cool to 0-5 ° C with an ice bath, add 7 mg of diisopropylethylamine and stir for 10 minutes. Add 2.4 mg of ril chloride and react for 30 minutes. In an ice bath, add 100 ml of water to the reaction solution, extract three times with chloroform (5 ml × 3), collect the chloroform layer, wash once with saturated brine, dry over anhydrous magnesium sulfate, filter and rotate Remove the solvent at Purify by thin layer chromatography and develop with chloroform, methanol = 95: 5. 8 mg of the product obtained is dissolved in 3 ml of DMF (anhydrous), cooled to −5 to 0 ° C. with an ice bath through argon, added with 0.3 mg of sodium hydride and stirred for 24 hours. After completion of the reaction, 50 ml of water was added, extracted three times with chloroform (5 ml × 3), the chloroform layer was collected, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered and rotated to remove the solvent Remove. Purification by thin layer chromatography and development with chloroform, methanol = 30: 1 gave 6 mg product, MS: 611.

[Example 13]
3'-Pyrroladriamycin-14-oxygen-succinic acid monoester
Add 845 g of 3′-pyrrole adriamycin to a 50 ml single-necked flask, dissolve in 20 ml of chloroform, cool to −10 ° C. under an argon atmosphere, add 704 mg of DMAP and 570 mg of succinic anhydride, and stir with stirring. After completion of the reaction, 300 ml of chloroform was added to the reaction solution, washed once with 100 ml of 5% aqueous citric acid solution, washed once with 100 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and spin-dried to obtain a crude product. It is done. Purification by column chromatography eluting with chloroform: methanol: glacial acetic acid = 475: 25: 5 gave 238 mg of product, MS: 692 (M-1).

  The compounds shown in Examples 14 to 25 are synthesized by the same method.

Example 14
3'-pyrrole-esorubicin-14-oxygen-succinic acid monoester, MS: 676 (M-1).

[Example 15]
3'-pyrrol-4 '-(pyran-2-yl) adriamycin-14-oxygen-succinic acid monoester, MS: 776 (M-1).

[Example 16]
3'-succinimide adriamycin-14-oxygen-succinic acid monoester, MS: 724 (M-1).

[Example 17]
3'-glutarimide adriamycin-14-oxygen-succinic acid monoester, MS: 738 (M-1).

[Example 18]
3'-cis-butenediimide adriamycin-14-oxygen-succinic acid monoester, MS: 722 (M-1).

[Example 19]
3 '-(pyrrolo- (2,3) succinimide) adriamycin-14-oxygen-succinic acid monoester, MS: 773 (M-1).

[Example 20]
3 '-(Benzo- (2,3) succinimide) adriamycin-14-oxygen-succinic acid monoester, MS: 772 (M-1).

[Example 21]
3'-pyrrole adriamycin-14,4'-oxygen-disuccinic acid monoester, MS: 792 (M-1).

[Example 22]
3'-pyrrole adriamycin-14-oxygen-cis-butenedioic acid monoester, MS: 690 (M-1).

[Example 23]
3'-pyrrole adriamycin-14,4'-oxygen-di-cis-butenedioic acid monoester, MS: 788 (M-1).

[Example 24]
3′-pyrrole adriamycin-14-oxygen-glutaric acid monoester, MS: 730 (M + Na).

[Example 25]
3′-pyrrole adriamycin-14,4′-oxygen-diglutaric acid monoester MS: 820 (M-1).

[Example 26]
3'-Pyrroladriamycin-14-oxygen- (3-nitro-2-carboxyl) benzoate
Add 50 mg of 3′-pyrrole adriamycin to a 50 ml single-necked flask, dissolve in 2.5 ml of chloroform, cool to −5 ° C. under an argon atmosphere, add 42 mg of DMAP and 65 mg of 3-nitrophthalic anhydride, and stir with stirring. After completion of the reaction, 150 ml of chloroform was added to the reaction solution, washed once with 100 ml of 5% citric acid, and the organic phase was washed once with 100 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and spin-dried, diluted. Purification by layer chromatography eluting with chloroform: methanol: glacial acetic acid = 450: 50: 5 gives the desired compound. MS: 785 (M-1).

  The compounds shown in Examples 27 to 37 are synthesized by the same method.

[Example 27]
3′-pyrrole adriamycin-14-oxygen- (3-fluorine-2-carboxyl) benzoate, MS: 785 (M-1).

[Example 28]
3′-pyrrole adriamycin-14,4′-oxygen-di (3-fluorine-2-carboxyl) benzoate, MS: 925.

[Example 29]
3'-pyrrole adriamycin-14-oxygen- (2-carboxyl-6-fluorine) benzoate, MS: 785 (M-1).

[Example 30]
3′-pyrrole adriamycin-14,4′-oxygen-di (6-fluorine-2-carboxyl) benzoate, MS: 925.

[Example 31]
3′-pyrrole adriamycin-14-oxygen- (3,4,5,6-tetrafluoro-2-carboxyl) benzoate, MS: 812 (M-1).

[Example 32]
3′-pyrrole adriamycin-14,4′-oxygen-di (3,4,5,6-tetrafluorine-2-carboxyl) benzoate, MS: 1033 (M).

[Example 33]
3'-pyrrole adriamycin-14-oxygen- (2,4-dicarboxyl) benzoate group, MS: 784 (M-1).

[Example 34]
3′-pyrrole adriamycin-14,4′-oxygen-di (2,4-dicarboxyl) benzoate, MS: 978 (M).

[Example 35]
3′-pyrrole adriamycin-14,4′-oxygen-di (2-carboxyl) benzoate, MS: 889 (M).

[Example 36]
3′-pyrrole adriamycin-14-oxygen- (3-carboxyl) pyridine-2-formate, MS: 741 (M-1).

[Example 37]
3′-pyrrole adriamycin-14,4′-oxygen- (3-nitro-2-carboxyl) dibenzoate, MS: 978 (M-1).

[Example 38]
3'-pyrrole adriamycin-14-oxygen-alanine ester hydrochloride
Add 59.3 mg of 3′-pyrrole adriamycin and 10 ml of dichloromethane (dried molecular sieve) to a 50 ml one-necked flask, stir in an argon atmosphere, and add 63 mg of Boc-alanine, 38 mg of EDC HCl, and 12 mg of DMA. After completion of the reaction, 50 ml of dichloromethane was added, washed with 100 ml of water, the aqueous layer was back-extracted once with dichloromethane, the organic phase was collected, the resulting organic phase was washed once with 100 ml of saturated brine, and anhydrous magnesium sulfate , Filtered, spin-dried, purified by thin layer chromatography and developed with chloroform: methanol = 35: 1 to give 43 mg of product. The resulting compound is dissolved in 1 ml of tetrahydrofuran (double-distilled), and argon gas is flowed, the temperature is lowered to −5 ° C., 1 ml of an ethyl ether solution of hydrogen chloride is added, and the mixture is stirred at room temperature for 2 hours. Filter and wash the filter cake three times with ethyl ether to give the desired compound.

  The compounds shown in Examples 39 to 53 are synthesized by the same method.

[Example 39]
3'-pyrrole adriamycin-14-oxygen-valine ester hydrochloride,

[Example 40]
3′-pyrrole adriamycin-14-oxygen-glycine ester hydrochloride,

[Example 41]
3'-pyrrole adriamycin-14-oxygen-leucine ester hydrochloride,

[Example 42]
3′-pyrrole adriamycin-14-oxygen- (2,2-dimethyl) glycine ester hydrochloride,

[Example 43]
3′-pyrrole adriamycin-14-oxygen- (2-phenyl) glycine ester hydrochloride,

[Example 44]
3'-pyrrole adriamycin-14-oxygen-diethylaminoacetate,

[Example 45]
3'-pyrrole adriamycin-14-oxygen-morpholine acetate,

[Example 46]
3′-pyrrole adriamycin-14-oxygen- (N-glycyl) valine ester hydrochloride,

[Example 47]
3'-pyrrole-esorubicin-14-glycine ester hydrochloride,

[Example 48]
3′-pyrrole-4 ′-(pyran-2-yl) adriamycin-14-oxygen-glycine ester hydrochloride,

[Example 49]
3′-succinimide adriamycin-14-oxygen-glycine ester hydrochloride,

[Example 50]
3'-glutarimide adriamycin-14-oxygen-glycine ester hydrochloride,

[Example 51]
3'-cis-butenediimide adriamycin-14-oxygen-glycine ester hydrochloride,

[Example 52]
3 '-(pyrrolo- (2,3) succinimide) adriamycin-14-oxygen-glycine ester hydrochloride,

[Example 53]
3 '-(benzo- (2,3) succinimide) adriamycin-14-oxygen-glycine ester hydrochloride, or

[Example 54]
3'-pyrrole adriamycin-14-oxygen-beta-alanine ester hydrochloride

[Measurement of cytotoxicity (MTS Assay)]
1． Cell lines and reagents
MCF-7, human breast cancer cell line,
HCT-8, human colon cancer cell line,
HEPG-2, human liver cancer cell line,
A549, human lung cancer cell line,
LOVO, human colon cancer cell line,
RPMI 1460 medium, MTT, blue tetrazolium, DMSO, dimethyl sulfoxide, 96-well cell culture plate,
Anti-tumor compounds (synthesized from Tianjin Kazumi Biological Technology Co., Ltd.),
Positive control drug-Adriamycin (Zhejiang Haisho Pharmaceutical Co., Ltd.).

2． Measurement of cell growth inhibitory activity
(1) cell culture and drug treatment,
Cells are inoculated into RPMI 1640 cell culture medium containing 10% fetal bovine serum (supplemented with 100 ku / L each of penicillin and streptomycin), and the culture plate is left at 37 ° C. in a cell incubator containing 5% CO _2. Change the solution once every 2-3 days, digest with 0.25% trypsin, passaging and cell harvesting.

  Using an RPMI 1640 cell culture medium containing 10% fetal bovine serum, cells in the logarithmic growth phase are produced in a predetermined concentration of cell suspension, and there are cell suspensions with 3000-5000 cells / 100 μl per well. After suspending the suspension in a 96-well plate and culturing for 24 hours, 100 μl of each sample having a different concentration is added to each well. After culturing for 72 to 120 hours, discard the detachment solution, place 100 μl of 0.5 mg / ml MTT serum-free culture solution newly prepared in each well, and incubate at 37 ° C for 4 hours to remove the detachment solution. throw away. Dissolve formazan with 200 μl DMSO, shake lightly for 15 minutes, and then measure the light absorption value (OD-value) with a microplate reader at a measurement frequency of 570 nm and a reference frequency of 450 nm.

(2) Data processing,
The data is displayed in x ± s,
Inhibition rate = (target group OD-value−administration group OD-value) / target group OD-value × 100%,
The anti-cancer effect is displayed using the maximum inhibition rate I _MAX and the semi-effective concentration (IC ₅₀ ). Graph with MicroCal Origin salt, and with the four parameter Logistic program in the salt, create a suppression curve of a suitable test sample against tumor cell growth and have a semi-effective concentration (IC ₅₀ , μg / ml) to suppress tumor cell growth Ask.

(3) Results The exposure concentration of the test product is 0.001 μg / ml, 0.003 μg / ml, 0.009 μg / ml, 0.027 μg / ml, 0.082 μg / ml, 0.247 μg / ml, 0.741 μg / ml, 2.222 μg / ml. 6.667 μg / ml, 20 μg / ml,
Exposure concentrations of adriamycin (positive drug) are 1.25 μg / ml, 5 μg / ml, and 20 μg / ml. In a 96-well plate, 3000-5000 cells are inoculated per hole, and there are four parallel holes for each concentration. Table 1 shows the growth inhibition rate of the compound against Lovo cells at a concentration of 1 μM, Table 2 shows the inhibitory activity of the compound on multiple tumor cells, and Table 3 shows the compound MCF-7 at different concentrations. The suppression rate with respect to a breast adenocarcinoma cell proliferation is shown.

  Compared to the activity of adriamycin, the activity of the test compound is comparable or slightly better, and various human tumor cell lines such as human colon cancer LOVO, human breast cancer MCF-7, colon cancer HCT-8, liver cancer HEPG -2 Has a relatively strong growth inhibitory effect on the lung cancer A549 cell line.

[MTD test report in mouse body of Example 1]
The experimental purpose, fundamentally, the toxicity in the mouse body of Example 1 will be considered.
Experimental animals, Kunming mice 20 ± 2g, purchased from the Animal Care Room, Institute of Radiological Sciences, Chinese Academy of Medical Sciences, Animal License Number SCXK (Tsu) 2005-0001
Experimental drug, Example 1
Preparation of drug solution, after swirling 0.5% by volume of DMSO, 5% by volume of RH40 (polyoxyethylene hydrogenated castor oil) is added, swirled uniformly, and then fixed with physiological saline.

Experimental plan,
(1) One dose, 9 healthy Kunming mice (weight, 20 ± 2g) are selected, and the blank groups (2), 20mg / kg (6) and 30mg / kg (1) Divide into three groups. Reference is made by administering 20 mg / kg and 30 mg / kg of Example 1 at a time to the administration group by tail vein administration, and administering a corresponding volume of solvent to the blank group. After administration, the mice are observed for behavior, reflex and spontaneous activity within 1 hour, and thereafter the body weight of the mice is recorded daily. After cessation of administration, observe for 14 days and dissect to see if there are any obvious abnormalities in major organs.

  (2) Several doses, 12 healthy Kunming mice (weight, 20 ± 2g) are selected and divided into two groups: a blank group (1 mouse) and 10 mg / kg (5 animals). To the administration group, administer the 10 mg / kg reagent once in the manner of tail vein administration every three days, and administer the corresponding volume of solvent to the blank group and refer to each group. Administer 5 times, and after each dose, observe the behavior, reflex and spontaneous activity within 1 hour of the mouse and record the weight of the mouse every day. After stopping administration, after feeding normally for one week, dissect and observe whether there are obvious abnormalities in major organs.

Experimental result,
1, mortality,
(1) No single dose or death was confirmed.
(2) Several times of administration, death was not confirmed.
2, weight change,
(1) The body weight of the mice administered and administered once showed a tendency to increase, and there was no abnormality on the body surface.
(2) The increase in the body weight of the mice administered several times was moderate, and there was no abnormality on the body surface. .

  In mice, the maximum tolerated dose (MTD) of the test compound is at least 5 times higher than adriamycin (MTD, 8-12 mg / kg).

Claims (17)

(Of which,
R ¹ represents H, C _1-4 hydrocarbon group or OC _1-4 hydrocarbon group,
R ² represents H or OR ⁶ , wherein R ⁶ is H, C (O) R ⁸ , peptide chain, C (O) NH ₂ , C (O) NR ⁸ R ⁹ , C (O) Ar— R ²⁷ , C (O) (C _2-4 alkylene group) COOH or a group represented by the formula (II), R ⁸ and R ⁹ each represent H, C _1-6 hydrocarbon group, or NR ⁸ R ^{9 represents} pyrrolidin-1-yl, piperidin-1-yl or morpholin-1-yl, Ar represents an aromatic ring or a heterocyclic aromatic ring, R ²⁷ represents 0 to 5 same or different F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbon group, OC _1-6 hydrocarbon group, OC (O) C _1-6 hydrocarbon group, C (O) OC _1-6 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon group or S (O) ₂ C _1-6 hydrocarbon group A peptide chain consisting of one natural amino acid, an unnatural amino acid, or 2 to 4 natural amino acids and / or unnatural amino acids,
W represents O or NH;
R ³ is H, F, OC _1-4 hydrocarbon group or C _1-4 hydrocarbon group,
R ⁴ represents H, F, C _1-4 hydrocarbon group or OR ⁷ , wherein R ⁷ represents H, 2-pyranyl or R ⁶ ;
R ⁵ is represented by formula (III), formula (IV), formula (V) or maleimide,
n represents 1 or 2,
X and Y each represent C = O or CR ²¹ R ²² ;
Q represents CH or N;
R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ are H, F, Cl, CN, NO ₂ , NH ₂ , OH, C (O) OC _1-4 hydrocarbon group, OC (O ) C _1-4 hydrocarbon group, OC _1-4 hydrocarbon group, C _1-4 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon group, S (O) ₂ C _1-6 hydrocarbon group, C (O) Ar-R ²⁷ , or NR ⁸ R ⁹ is shown,
R ²¹ and R ²² each represent H or C _1-4 hydrocarbon group,
However, X and Y do not indicate CH ₂ at the same time. )
A compound represented by the above formula (I) or a salt or solvate thereof. The compound represented by the formula (I) of claim 1, wherein R ¹ represents H, OH or OCH ₃ , a salt or a solvate thereof.   2. The compound represented by the formula (I), a salt or a solvate thereof according to claim 1, wherein W represents O. R ² is H, OH, succinic acid monoester group, glutaric acid monoester group, butenedioic acid monoester group, (3-nitro-2-carboxyl) benzoic acid ester group, (3-fluorine-2-carboxyl) benzoic acid Acid ester group, (2-carboxyl-6-fluorine) benzoic acid ester group, (3,4,5,6-tetrafluoro-2-carboxyl) benzoic acid ester group, (2,4-dicarboxyl) benzoic acid ester Group, (2-carboxyl) benzoic acid ester group, (3-carboxyl) pyridine-2-formic acid ester group, alanine ester group, valine ester group, glycine ester group, leucine ester group, (2,2-dimethyl) glycine ester A compound represented by formula (I) in claim 1, which represents a group, (2-phenyl) glycine ester group, 2-diethylaminoacetate group, 2-morpholine acetate group or (N-glycyl) valine ester group , Salt or solvate thereof. 2. The compound represented by the formula (I), a salt or a solvate thereof according to claim 1, wherein R ³ represents H or CH ₃ . R ⁴ is H, F, OH, OCH ₃ , 2-pyranyl group, succinic acid monoester group, (3-nitro-2-carboxyl) benzoic acid ester group, (2-carboxyl) benzoic acid ester group, (2, 4-dicarboxyl) benzoic acid ester group, (3,4,5,6-tetrafluoro-2-carboxyl) benzoic acid ester group, (2-carboxyl-6-fluorine) benzoic acid ester group, (3-fluorine- The compound represented by the formula (I) according to claim 1, a salt or solvate thereof, which represents a 2-carboxyl) benzoic acid ester group. R ⁵ is pyrrol-1-yl, succinimide group, glutarimide group, butyrolactam-1-yl, valerolactam-1-yl, phthalimide group or pyridinephthalimide group, the compound represented by formula (I) of claim 1, The salt or solvate. The compound is
3'-Pyrrolyl doxorubicin,
3'-pyrrolyl-5-iminodaunomycin,
3'-pyrrolyl-idarubicin,
3'-pyrrolyl-esorubicin,
3'-Pyrrolyl doxorubicin,
3'-pyrrolyl-4 '-(pyran-2-yl) doxorubicin,
3'-succinimide doxorubicin,
3'-glutarimide doxorubicin,
3'-cis-butenediimide doxorubicin,
3 '-(pyrrolo- (2,3) succinimide) doxorubicin,
3 '-(benzo- (2,3) succinimide) doxorubicin,
3'-butyrolactam doxorubicin,
3'-pyrrole-esorubicin-14-oxo-succinic acid monoester,
3'-pyrrole-4 '-(pyran-2-yl) doxorubicin-14-oxo-succinic acid monoester,
3′-succinimide doxorubicin-14-oxo-succinic acid monoester,
3′-glutarimide doxorubicin-14-oxo-succinic acid monoester,
3'-cis-butenediimide doxorubicin-14-oxo-succinic acid monoester,
3 ′-(pyrido- (2,3) succinimide) doxorubicin-14-oxo-succinic acid monoester,
3 '-(benzo- (2,3) succinimide) doxorubicin-14-oxo-succinic acid monoester,
3′-pyrrolyldoxorubicin-14,4′-oxo-disuccinic acid monoester,
3′-Pyrrolyl doxorubicin-14-oxo-cis-butenedioic acid monoester,
3′-pyrrolyldoxorubicin-14,4′-oxo-di-cis-butenedioic acid monoester,
3'-pyrrolyldoxorubicin-14-oxo-glutaric acid monoester,
3′-pyrrolyldoxorubicin-14,4′-oxo-diglutaric acid monoester,
3'-Pyrrolyl doxorubicin-14-oxo- (3-nitro-2-carboxyl) benzoate,
3′-pyrrolyldoxorubicin-14-oxo- (3-fluorine-2-carboxyl) benzoate,
3′-pyrrolyldoxorubicin-14,4′-oxo-bis (3-fluorine-2-carboxyl) benzoate,
3'-pyrrolyldoxorubicin-14-oxo- (2-carboxyl-6-fluorine) benzoate,
3′-pyrrolyldoxorubicin-14,4′-oxo-bis (6-fluorine-2-carboxyl) benzoate,
3′-Pyrrolyl doxorubicin-14-oxo- (3,4,5,6-tetrafluoro-2-carboxyl) benzoate,
3′-pyrrolyldoxorubicin-14,4′-oxo-bis (3,4,5,6-tetrafluoro-2-carboxyl) benzoate,
3′-pyrrolyl doxorubicin-14-oxo- (2,4-dicarboxyl) benzoate group,
3′-pyrrolyldoxorubicin-14,4′-oxo-bis (2,4-dicarboxyl) benzoate,
3′-pyrrolyldoxorubicin-14,4′-oxo-bis (2-carboxyl) benzoate,
3′-pyrrolyldoxorubicin-14-oxo- (3-carboxyl) pyridine-2-formate,
3′-pyrrolyldoxorubicin-14,4′-oxo- (3-nitro-2-carboxyl) dibenzoate,
3'-Pyrrolyl doxorubicin-14-oxo-alanine ester hydrochloride,
3′-pyrrolyl doxorubicin-14-oxo-valine ester hydrochloride,
3'-pyrrolyldoxorubicin-14-oxo-glycine ester hydrochloride,
3'-pyrrolyldoxorubicin-14-oxo-leucine ester hydrochloride,
3′-pyrrolyldoxorubicin-14-oxo- (2,2-dimethyl) glycine ester hydrochloride,
3′-pyrrolyldoxorubicin-14-oxo- (2-phenyl) glycine ester hydrochloride,
3′-pyrrolyl doxorubicin-14-oxo-2-diethylaminoacetate,
3'-Pyrrolyl doxorubicin-14-oxo-morpholine acetate,
3'-pyrrolyldoxorubicin-14-oxo- (N-glycyl) valine ester hydrochloride,
3'-pyrrolyl-esorubicin-14 oxo-glycine ester hydrochloride,
3′-pyrrolyl-4 ′-(pyran-2-yl) doxorubicin-14-oxo-glycine ester hydrochloride,
3′-succinimide doxorubicin-14-oxo-glycine ester hydrochloride,
3'-glutarimide doxorubicin-14-oxo-glycine ester hydrochloride,
3'-cis-butenediimide doxorubicin-14-oxo-glycine ester hydrochloride,
3 '-(pyrido- (2,3) succinimide) doxorubicin-14-oxo-glycine ester hydrochloride,
3 '-(benzo- (2,3) succinimide) doxorubicin-14-oxo-glycine ester hydrochloride, or
2. The compound or solvate represented by the formula (I) according to claim 1, which is 3′-pyrrolyldoxorubicin-14-oxo-β-alanine ester hydrochloride. A process for producing a compound represented by formula (I) of claim 1,

The group represented by R ¹ , R ³ , R ⁴ and W in the compound represented by the formula (VII) is a group represented by R ¹ , R ³ , R ⁴ and W in the compound represented by the formula (I) of claim 1. R ²⁰ represents H or OH,
Group represented by ^{R 1, R 3, R 4} , R 5 and W in a compound represented by formula (VI), R ¹ in the compound represented by formula (I) according to claim ^{1, R 3, R 4,} R ^The same as the group represented by ⁵ and W ; wherein R ⁵ is represented by formula (V); R ²⁰ represents H or OH ;
The group represented by R ¹⁶ in the compound represented by the formula (VIII) is the same as the group represented by R ¹⁶ in the compound represented by the formula (V) of claim 1, and R ²¹ and R ²² are each H or C _{1. -4 represents a} hydrocarbon group,
The compound represented by the formula (VII) or a salt thereof reacts with the compound represented by the above formula (VIII) in the presence of an acidic and / or alkaline reagent to obtain the compound represented by the formula (VI),
When R ²⁰ represents OH, the compound represented by formula (VI) is R ⁸ COOH, peptide chain, HOOC-Ar-R ²⁷ , compound represented by formula (IX), compound represented by formula (XV), Reacting with a compound represented by the formula (XXI) or R ⁸ NCO to obtain a compound represented by the formula (I),
here,
R ⁸ in R ⁸ COOH represents a C _1-6 hydrocarbon group, R ⁸ and R ²⁶ in the compound represented by formula (XXI) represents H or C _1-6 hydrocarbon groups, respectively, Ar is an aromatic ring or R ²⁷ represents the same or different F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbon group, 0 to 5 OC _1-6 hydrocarbon group, OC (O) C _1-6 hydrocarbon group, C (O) OC _1-6 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon Group or S (O) ₂ C _1-6 hydrocarbon group,
The peptide chain has a free carboxyl group and has 0-2 identical or different C _1-6 hydrocarbon groups at the N-terminus, or is selected from the group consisting of Fmoc, Boc, CBZ, Tr and Alloc A production method comprising a protective group for an amino group.   Use of the compound represented by the formula (I) according to any one of claims 1 to 8 and a salt or solvate thereof in the manufacture of a drug for abnormal cell proliferation disease.   11. The use according to claim 10, wherein the cell proliferation abnormality disease is a tumor or cancer.   The abnormal cell proliferation diseases include liver cancer, stomach cancer, breast cancer, lung cancer, intestinal cancer, ovarian cancer, pancreatic cancer, head and neck cancer, cervical cancer, kidney cancer, melanoma, prostate cancer, glioma, various leukemias, lymph 11. The use according to claim 10, which is cancer or multiple myeloma.   Use according to claim 10, wherein the compound of formula (I), salt or solvate thereof is an injectable preparation.   14. Use according to claim 13, wherein the injectable formulation is selected from the group consisting of powder injections, lyophilized powder injections, water needles, emulsions and suspensions. A process for producing a compound represented by formula (I) of claim 1,

R ^10, R ¹¹ in the compound represented by formula (IX), R ^12, a group represented by R ¹³ and n are, R ^10, R ¹¹ in the compound represented by formula (III) according to claim 1, R ^12, R ^The group represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and n in the compound represented by the formula (X) is the same as the group represented by ¹³ and n, and the group represented by the formula (III) in claim 1 The group represented by R ¹ , R ³ , R ⁴ and W in the compound represented by the formula (X) which is the same as the group represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and n is represented by the formula (VII). The same as the group represented by R ¹ , R ³ , R ⁴ and W in the compound, R ²⁰ represents H or OH,
A compound represented by formula (VII) or a salt thereof reacts with a compound represented by formula (IX) to obtain a compound represented by formula (X), and the compound represented by formula (X) is subjected to the action of a dehydrating agent. To give a compound of formula (VI)
When R ²⁰ represents OH, the compound represented by formula (VI) is R ⁸ COOH, peptide chain, HOOC-Ar-R ²⁷ , compound represented by formula (IX), compound represented by formula (XV), Reaction with a compound represented by formula (XXI) or R ⁸ NCO yields a compound represented by formula (I), wherein R ⁵ is a compound represented by formula (III) wherein X and Y each independently represent C═O. ); Or indicated by maleimide,
here,
R ⁸ in R ⁸ COOH represents a C _1-6 hydrocarbon group,
R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each represent H or C _1-6 hydrocarbon group,
Ar represents an aromatic ring or a heterocyclic aromatic ring,
R ²⁷ is the same or different from 0 to 5 F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbon group, OC _1-6 hydrocarbon group, OC (O) C _1-6 hydrocarbon group, C (O) OC _1-6 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon group or S (O) ₂ C _{1 -6 represents a} hydrocarbon group,
The peptide chain has a free carboxyl group, and 0 to 2 identical or different C _1-6 hydrocarbon groups or an amino group protecting group selected from Fmoc, Boc, CBZ, Tr or Alloc is present at the N-terminus. The manufacturing method characterized by having. A process for producing a compound represented by formula (I) of claim 1,

R ^10, R ¹¹ in the compound represented by formula ^{(XIV), R 12, R} 13, R 21, a group represented by R ²² and n are, R ^10, in the compound represented by formula (III) of claim 1 R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² and n are identical to the group represented by
The compound represented by formula (XIV) reacts with the compound represented by formula (VII) or a salt thereof under the action of an alkaline reagent and / or an acidic reagent to obtain a compound represented by formula (VI),
When R ²⁰ represents OH, the compound represented by formula (VI) is R ⁸ COOH, peptide chain, HOOC-Ar-R ²⁷ , compound represented by formula (IX), compound represented by formula (XV), Reaction with a compound represented by formula (XXI) or R ⁸ NCO yields a compound represented by formula (I), wherein R ⁵ is a compound represented by formula (III) wherein X and Y each independently represent C═O. ) And
here,
R ⁸ in R ⁸ COOH represents a C _1-6 hydrocarbon group,
R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each represent H or C _1-6 hydrocarbon group,
Ar represents an aromatic ring or a heterocyclic aromatic ring,
R ²⁷ is the same or different from 0 to 5 F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbon group, OC _1-6 hydrocarbon group, OC (O) C _1-6 hydrocarbon group, C (O) OC _1-6 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon group or S (O) ₂ C _{1 -6 represents a} hydrocarbon group,
The peptide chain has a free carboxyl group, and 0 to 2 identical or different C _1-6 hydrocarbon groups or an amino group protecting group selected from Fmoc, Boc, CBZ, Tr or Alloc is present at the N-terminus. The manufacturing method characterized by having. A process for producing a compound represented by formula (I) of claim 1,

The group represented by R ¹⁵ and Q in formula (XV) is the same as the group represented by R ¹⁵ and Q in formula (IV) of claim 1,
The group represented by R ¹⁵ and Q in formula (XVI) is the same as the group represented by R ¹⁵ and Q in formula (IV) of claim 1,
Group represented by ^{R 1, R 3, R 4} , R 20 and W in the formula (XVI) may, R ¹ in the compound represented by formula ^{(VII), R 3, R} 4, R 20 and W same as the group represented by And
The group represented by R ¹⁵ and Q in the formula (XVII) is the same as the group represented by R ¹⁵ and Q in the formula (IV) of claim 1,
Formula (XVII) in ^{R 1, R 3, R 4} , R 20 and W is a group shown is identical to the group indicated by ^{R 1, R 3, R 4} , R 20 and W in a compound represented by formula (VII) And
A compound represented by formula (XVI) or (XVII) reacts under the action of a dehydrating agent to obtain a compound represented by formula (VI),
When R ²⁰ represents OH, the compound represented by formula (VI) is R ⁸ COOH, peptide chain, HOOC-Ar-R ²⁷ , compound represented by formula (IX), compound represented by formula (XV), Reaction with a compound of formula (XXI) or R ⁸ NCO yields a compound of formula (I), wherein R ⁵ is represented by formula (IV),
here,
R ⁸ in R ⁸ COOH represents a C _1-6 hydrocarbon group,
R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each represent H or C _1-6 hydrocarbon group,
Ar represents an aromatic ring or a heterocyclic aromatic ring,
R ²⁷ is the same or different from 0 to 5 F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbon group, OC _1-6 hydrocarbon group, OC (O) C _1-6 hydrocarbon group, C (O) OC _1-6 hydrocarbon group, SC _1-6 hydrocarbon group, S (O) C _1-6 hydrocarbon group or S (O) ₂ C _{1 -6 represents a} hydrocarbon group,
The peptide chain has a free carboxyl group, and 0 to 2 identical or different C _1-6 hydrocarbon groups or an amino group protecting group selected from Fmoc, Boc, CBZ, Tr or Alloc is present at the N-terminus. The manufacturing method characterized by having.