KR101328315B1 - Anthracycline antibiotic derivatives with high activity, preparation methods and uses thereof - Google Patents

Abstract

The present invention relates to tetracyclic anthraquinone antibiotic derivatives having anticancer activity. Tetracyclic anthraquinone antibiotic derivatives provided herein have the same or higher resistance than doxorubicin, daunorubicin and the like at the cellular level while having better resistance than doxorubicin and daunorubicin in the body of an animal. Have activity.

Description

ANTHRACYCLINE ANTIBIOTIC DERIVATIVES WITH HIGH ACTIVITY, PREPARATION METHODS AND USES THEREOF}

The present invention relates to tetracyclic anthraquinone antibiotic derivatives having anticancer activity, methods of making them, and their use in the manufacture of a medicament for treating a tumor or cancer.

Tetracyclic anthraquinone antibiotics, especially doxorubicin and daunorubicin, are widely used anticancer agents. Doxorubicin has a significant therapeutic effect on many solid cancers, including liver cancer, stomach cancer, breast cancer, lung cancer, ovarian cancer and multiple leukemias. Daunorubicin is one of the most effective drugs for treating leukemia. However, due to their side effects such as severe myelosuppression, cardiotoxicity, side effects of the digestive tract, their clinical applications are limited. To date, many tetracyclic anthraquinone derivatives have already been isolated from nature or manufactured artificially. We want to get a new generation of anticancer drugs with high activity and low toxicity from these derivatives. Attila A. The activity at the cellular level of the doxorubicin derivative 2-pyrrolinyl-doxorubicin (AN-201) prepared by Attila A. Nagy, et al. Is 300-1000 times that of doxorubicin. However, due to the high toxicity of AN-201, no anticancer activity was observed at the maximum tolerated dose in the pathological model of tumors implanted in mice.

summary

The present invention relates to tetracyclic anthraquinone antibiotic derivatives having anticancer activity. Tetracyclic anthraquinone antibiotic derivatives provided herein have the same or higher resistance than doxorubicin, daunorubicin and the like at the cellular level while having better resistance than doxorubicin and daunorubicin in the body of an animal. Have activity.

Accordingly, the present invention relates to a compound represented by the following formula (I) and salts or solvates thereof:

(I)

Where

R ¹ represents H, C _1-4 hydrocarbyl or OC _1-4 hydrocarbyl;

R ² represents H or OR ⁶ , wherein R ⁶ represents 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 hydrocarbylidene) COOH and a compound represented by the following formula (II);

(II)

R ⁸ and R ⁹ each independently represent H or C _1-6 hydrocarbyl, or NR ⁸ R ⁹ is pyrrolidin-1-yl, piperidin-1-yl or morpholin-1-yl Represents; Ar represents an aromatic ring or an aromatic heterocyclic ring; R ²⁷ is F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbyl, OC _1-6 hydrocarbyl, OC (O) C _1-6 Consisting of hydrocarbyl, C (O) OC _1-6 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl and S (O) ₂ C _1-6 hydrocarbyl 0-5 identical or different groups selected from the group; The peptide chain represents a peptide chain consisting of a single natural amino acid, a single artificial amino acid or 2 to 4 natural amino acids and / or artificial amino acids;

W represents O or NH;

R ³ represents H, F, OC _1-4 hydrocarbyl or C _1-4 hydrocarbyl;

R ⁴ represents H, F, C _1-4 hydrocarbyl 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 maleimido,

(III) (IV) (V),

Where

n represents 1 or 2;

X and Y each independently represent C═O or CR ²¹ R ²² ;

Q represents CH or N;

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are each independently H, F, Cl, CN, NO ₂ , NH ₂ , OH, C (O) OC _1-4 hydrocarbyl, OC (O) C _1-4 hydrocarbyl, OC _1-4 hydrocarbyl, C _1-4 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl, S (O ) ₂ C _1-6 hydrocarbyl, (C _0-4 hydrocarbylidene) Ar-R ²⁷ and NR ⁸ R ⁹ ;

R ²¹ and R ²² each independently represent H or C _1-4 hydrocarbyl.

As used herein, the term C _1-4 hydrocarbyl may be straight-chain saturated or unsaturated hydrocarbyl or branched-chain saturated or unsaturated hydrocarbyl and may be F, Cl, CN, OH, NO ₂ , COOH, C _{1- 4} hydrocarbyl, NHC (O) C _1-6 hydrocarbyl, NHC (O) Ar—R ²⁷ and NR ⁸ R ⁹ may be substituted with 0 to 4 identical or different substituents. R ⁸ and R ⁹ each independently represent H or C _1-6 hydrocarbyl, or NR ⁸ R ⁹ is pyrrolidin-1-yl, piperidin-1-yl and morpholin-1-yl Selected from the group consisting of:

As used herein, the term C _2-4 hydrocarbylidene may be straight-chain saturated or unsaturated hydrocarbylidene or branched-chain saturated or unsaturated hydrocarbylidene and may be F, Cl, CN, OH, NO ₂ , COOH, C _1-4 hydrocarbyl, NHC (O) C _1-6 hydrocarbyl, NHC (O) Ar-R ²⁷ and NR ⁸ R ⁹ to be substituted with 0 to 3 identical or different substituents selected from the group consisting of Can be. R ⁸ and R ⁹ each independently represent H or C _1-6 hydrocarbyl, or NR ⁸ R ⁹ is pyrrolidin-1-yl, piperidin-1-yl and morpholin-1-yl Selected from the group consisting of:

As used herein, the term C _0-4 hydrocarbylidene may be straight-chain saturated or unsaturated hydrocarbylidene or branched-chain saturated or unsaturated hydrocarbylidene and may be F, Cl, CN, OH, NO ₂ , COOH, C _1-4 hydrocarbyl, NHC (O) C _1-6 hydrocarbyl, NHC (O) Ar-R ²⁷ and NR ⁸ R ⁹ to be substituted with 0 to 3 identical or different substituents selected from the group consisting of Can be. R ⁸ and R ⁹ each independently represent H or C _1-6 hydrocarbyl, or NR ⁸ R ⁹ is pyrrolidin-1-yl, piperidin-1-yl and morpholin-1-yl Selected from the group consisting of:

As used herein, the term C _1-6 hydrocarbyl may be straight-chain saturated or unsaturated hydrocarbyl or branched-chain saturated or unsaturated hydrocarbyl and may be F, Cl, CN, OH, NO ₂ , COOH, C _{1- 4} hydrocarbyl, NHC (O) C _1-6 hydrocarbyl, NHC (O) Ar—R ²⁷ and NR ⁸ R ⁹ may be substituted with 0 to 4 identical or different substituents. R ⁸ and R ⁹ each independently represent H or C _1-6 hydrocarbyl, or NR ⁸ R ⁹ is pyrrolidin-1-yl, piperidin-1-yl and morpholin-1-yl Selected from the group consisting of.

The term aromatic ring or aromatic heterocyclic ring as used herein is selected from the group consisting of benzene, naphthalene, pyridine, pyrrole, thiophene, furan, pyrimidine and pyrazine.

Suitable for preparing a medicament for treating a tumor or cancer, the compound represented by formula (I) is a compound wherein R ¹ is selected from the group consisting of H, CH ₃ and OCH ₃ . The compound represented by the formula (I), which is most suitable for preparing a medicament for treating a tumor or cancer, is a compound in which R ¹ represents H or OCH ₃ .

Suitable for the manufacture of a medicament for treating a tumor or cancer, the compound represented by formula (I) is a compound in which R ² represents H or OR ⁶ , wherein R ⁶ is H, glycyl, alanyl, byl, Leucineyl, isoleucineyl, phenylalanyl, serineyl, threonyl, tyrosineyl, lysinyl, 2-N, N-dimethylaminoacetyl, 2-N, N-diethylaminoacetyl, 2-piperidylacetyl, 2-morpholinylacetyl, 2,2-dimethylglycyl, 2,2-dimethyl-2-methylaminoacetyl, 2,2-dimethyl-2- (N, N-dimethylamino) acetyl, 2,2-dimethyl 2-ethylaminoacetyl, 2,2-dimethyl-2- (N, N-diethylamino) acetyl, 2,2-dimethyl-2- (N, N-dipropylamino) acetyl, 2,2-dimethyl 2-piperidylacetyl, 2,2-dimethyl-2-pyrrolinylacetyl, 2,2-dimethyl-2-morpholinylacetyl, 2,2-dimethyl-2- (N-methyl-N-ethyl Amino) acetyl, 2-phenylglycyl, 2-phenyl-2-methylaminoacetyl, 2-phenyl-2- (N, N-dimethylamino) acetyl, 2-phenyl-2 -Ethylaminoacetyl, 2-phenyl-2- (N, N-diethylamino) acetyl, 2-phenyl-2- (N, N-dipropylamino) acetyl, 2-phenyl-2-piperidylacetyl, 2-phenyl-2-pyrrolinylacetyl, 2-phenyl-2-morpholinylacetyl, 2-phenyl-2- (N-methyl-N-ethylamino) acetyl, acetyl, propionyl, butan oil, pentane oil , 3-methylaminopropionyl, 3-ethylaminopropionyl, 3-N, N-dimethylaminopropionyl, 3-N, N-diethylaminopropionyl, 3-piperidylpropionyl, 3-pyrroli Dynylpropionyl, 3-morpholinylpropionyl, N-glycosylgylsil, N-alanylglycyl, N-balylglycyl, N-serinylglycyl, N-glycyalanyl, N-alanylalanyl , N-balylalanyl, N-serylylalanyl, N-glysilyl, N-alanylbalyl, N-balyl, N-serylyl, hydrogen succinate group, (3-nitro-2 -Carboxyl) benzoate group, (2-carboxyl) benzoate group, (2,4-dicarboxyl) benzoate group, (3,4,5,6-te A la-fluoro-2-carboxylic acid) is selected from a benzoate group, (2-carboxylic acid with 6-fluoro) benzoate group, and a (3-fluoro-2-carboxylic acid) benzoate group the group consisting of. More suitable for preparing a medicament for treating a tumor or cancer, the compound represented by formula (I) is a compound wherein R ² represents H or OR ⁶ , wherein R ⁶ is H, glycyl, alanyl, valyl , Leucineyl, isoleucineyl, phenylalanyl, serineyl, threonyl, tyrosineyl, lysinyl, 2-N, N-dimethylaminoacetyl, 2-N, N-diethylaminoacetyl, 2-piperidylacetyl , 2-morpholinylacetyl, 2,2-dimethylglycyl, 2-phenylglycyl, 3-methylaminopropionyl, 3-ethylaminopropionyl, hydrogen succinate group, (3-nitro-2-car Carboxyl) benzoate group, (2-carboxyl) benzoate group, (2,4-dicarboxyl) benzoate group, (3,4,5,6-tetrafluoro-2-carboxy)) benzoate group , (2-carboxy-6-fluoro) benzoate group and (3-fluoro-2-carboxyl) benzoate group. The compound represented by formula (I), which is most suitable for preparing a medicament for treating a tumor or cancer, is a compound in which R ² represents H or OR ⁶ , wherein R ⁶ is H, glycyl, alanyl, valyl , Leucineyl, isoleucineyl, phenylalanyl, serineyl, threonyl, tyrosineyl, lysinyl, 2-N, N-dimethylaminoacetyl, 2-N, N-diethylaminoacetyl, 2-piperidylacetyl , 2-morpholinylacetyl, 2,2-dimethylglycyl, 2-phenylglycyl, hydrogen succinate group, (3-nitro-2-carboxyl) benzoate group, (2-carboxyl) benzoate Group, (2,4-dicarboxyl) benzoate group, (3,4,5,6-tetrafluoro-2-carboxy) benzoate group, (2-carboxyl-6-fluoro) benzoate Group and (3-fluoro-2-carboxyl) benzoate group.

Compounds represented by formula (I), which are suitable for the manufacture of a medicament for treating a tumor or cancer, are compounds wherein W represents O or NH. The compound represented by the formula (I), which is most suitable for preparing a medicament for treating a tumor or cancer, is a compound in which W represents O.

Compounds represented by formula (I), which are suitable for the manufacture of a medicament for treating a tumor or cancer, are selected from the group in which R ³ consists of H, F, CH ₃ , CH ₂ CH ₃ , OCH ₃ and OCH ₂ CH ₃ Compound. More suitable for preparing a medicament for treating a tumor or cancer, the compound represented by formula (I) is a compound wherein R ³ is selected from the group consisting of H, CH ₃ and OCH ₃ . The compound represented by the formula (I), which is most suitable for preparing a medicament for treating a tumor or cancer, is a compound in which R ³ represents CH ₃ .

Compounds represented by formula (I), which are suitable for the manufacture of a medicament for treating a tumor or cancer, are those wherein R ⁴ is H, F, OH, CH ₃ , OCH ₃ , 2-pyranyl, hydrogen succinate group, ( 3-nitro-2-carboxyl) benzoate group, (2-carboxyl) benzoate group, (2,4-dicarboxyl) benzoate group, (3,4,5,6-tetrafluoro-2 -Carboxyl) benzoate group, (2-carboxyl-6-fluoro) benzoate group and (3-fluoro-2-carboxyl) benzoate group. More suitable for preparing a medicament for treating a tumor or cancer, the compound represented by formula (I) is a compound wherein R ⁴ is selected from the group consisting of OH, OCH ₃ , 2-pyranyl and hydrogen succinate groups. The compound represented by formula (I), which is most suitable for preparing a medicament for treating a tumor or cancer, is a compound wherein R ⁴ is selected from the group consisting of OH, 2-pyranyl and hydrogen succinate groups.

Compounds represented by formula (I), which are suitable for the manufacture of a medicament for the treatment of a tumor or cancer, are those in which R ⁵ is pyrrole-1-yl, succinimido, glutarimido, butyrolactam-1-yl, valerian Rolactam-1-yl, 3-methyl-pyrrole-1-yl, 3-methoxy-pyrrole-1-yl, 3-methyl-succinimido, 3-methoxy-succinimido, 3-methyl-glu Tarimido, 3-methoxy-glutarimido, 3-methyl-butyrolactam-1-yl, 3-methoxy-butyrolactam-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 and pyrido Succinimido-1-yl. Compounds represented by formula (I), most suitable for preparing a medicament for treating a tumor or cancer, include R ⁵ is pyrrole-1-yl, succinimido, glutarimido, butyrolactam-1-yl and Is a compound selected from the group consisting of valerolactam-1-yl.

In the present invention, a compound having a chiral center but not specifically represented by the R or S configuration in the formulas in the specification and claims may be a compound of the R configuration, a compound of the S configuration, or a mixture thereof.

The protection scope of the present invention also includes prodrugs, salts or active metabolites of the compounds disclosed herein.

The present invention discloses several methods for preparing compounds represented by formula (VI), which are important intermediates of the compounds represented by formula (I).

Method 1:

(VII)

(VI) (VIII)

In the compounds represented by the general formula (VII) a group represented by R ^1, R ^3, R ⁴ and W is the same group shown in compounds of the formula (I) with R ^1, R ^3, R ⁴ and W. R ²⁰ represents H or OH. Formula represented by (VI) R ^1, in the compound represented by ^{R 3, R 4, R R} 1, R 3 5 , and groups represented by W in the compound represented by the formula ^{(I), R 4, R} 5 and W Same as the group. 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). R ²¹ and R ²² each independently represent H or C _1-4 hydrocarbyl.

Salts of the compounds represented by the term formula (VII) described herein are reacted with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, methylsulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid and mixtures thereof. It is a salt of the compound represented by general formula (VII).

The compound represented by the formula (VI) is obtained by reacting the compound represented by the formula (VII) or a salt thereof with the compound represented by the formula (VIII) in the presence of an acidic and / or basic reagent, wherein 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, malic acid and mixtures thereof. . The amount of the acidic reagent is 0.05 to 500 times (moles) of the compound represented by the formula (VII). A more suitable amount of the acidic reagent is 0.2 to 50 times (moles) of the compound represented by the formula (VII). The most suitable amount of the acidic reagent is 0.7 to 5 times (moles) of the compound represented by the formula (VII). The basic reagents are 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, di Potassium hydrogen phosphate, sodium lactate, potassium lactate, sodium propionate, potassium propionate, sodium butyrate, potassium butyrate, sodium succinate, potassium succinate, sodium valerate, potassium valerate, sodium glutarate, Potassium glutarate, triethylamine, trimethylamine, diisopropylethylamine, 4-dimethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine, pyridine, N-methylmorpholine and mixtures thereof Is selected from. The amount of the basic reagent is 0.05 to 500 times (moles) of the compound represented by the formula (VII). More suitable amounts of such basic reagents are from 0.2 to 50 times (moles) of the compound represented by the formula (VII). The most suitable amount of the basic reagent is 0.7 to 5 times (moles) of the compound represented by the formula (VII). The reaction temperature is -20 to 150 ℃. More suitable reaction temperature is -10 to 100 ℃. Most suitable reaction temperature is -10 to 80 ℃. The reaction was carried out with dichloromethane, chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, ethylene glycol monomenyl ether, ethanol, methanol, isopropanol, tetrahydrofuran, ethyl acetate, methyl acetate, methyl propio Nate, ethyl propionate, ethylene glycol diethyl ether, ethylene glycol monoethyl ether, N, N-diethylformamide, 1,2-dichloroethane, acetonitrile, water, a compound represented by formula (VIII) or a It is carried out in the same solvent as the mixture. If necessary, organic bases such as triethylamine, trimethylamine, diisopropylethylamine, 4-dimethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine, pyridine, N-methylmorpholine, and the like are added during the reaction. It can be used as a catalyst. When an organic base is used as a catalyst, the molar amount of the organic base is 0.01 to 2 times that of the compound represented by the formula (VII). More suitable molar amount of the said organic base is 0.05-0.2 times of the compound represented by general formula (VII). The feed molar ratio of the compound represented by the formula (VII) or a salt thereof to the compound represented by the formula (VIII) is from 1: 0.1 to 1: 10000. A more suitable feed molar ratio of the compound represented by the formula (VII) or a salt thereof to the compound represented by the formula (VIII) is from 1: 0.5 to 1: 1000. The most suitable feed molar ratio of the compound represented by the formula (VII) or a salt thereof to the compound represented by the formula (VIII) is 1: 1 to 1: 500.

A second method for preparing the compounds represented by formula (VI) disclosed herein is as follows:

    (IX) (X)

Wherein, the groups represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and n in the compound represented by the formula (IX) are represented by R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and same as the group represented by n; The formula shown in the compound represented by the (X) group represented by ^{R 10, R 11, R 12} , R 13 and n in the compound represented by the formula (III) with ^{R 10, R 11, R 12} , R 13 and n The same as the group being; Group shown in compounds of the formula (X) with R ^1, R ^3, R ⁴ and W are the same groups 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 (X) is obtained by reacting the compound represented by the formula (VII) or a salt thereof with the compound represented by the formula (IX). The reaction is dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, methyl propionate, ethyl propionate, 1,2-dichloroethane, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl It is carried out in a solvent such as ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide, acetonitrile, water or mixtures thereof. Pyridine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine or mixtures thereof can optionally be added as a catalyst to the reaction. The molar amount of the catalyst is 0.01 to 10 times that of the compound represented by the formula (VII). More suitable molar amount of the catalyst is from 0.02 to 5 times the compound represented by the formula (VII). The optimum molar amount of the catalyst is 0.05 to 1 times that of the compound represented by the formula (VII). Triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methyl piperidine, N-ethyl piperidine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (Pyrrolidin-1-yl) pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or mixtures thereof can be added to the reaction as an acid binder. have. The molar amount of the acid binder is 0.4 to 20 times that of the compound represented by the formula (VII). More suitable molar amount of the acid binder is 0.8 to 10 times the compound represented by the formula (VII). The optimum molar amount of the acid binder is 1 to 5 times the compound represented by the formula (VII). The reaction temperature is -20 to 100 ℃. More suitable reaction temperature is -10 to 80 ℃. The optimum reaction temperature is -5 to 80 ° C. The feed molar ratio of the compound represented by the formula (IX) to the compound represented by the formula (VII) or a salt thereof is from 1: 0.1 to 1:10. A more suitable feed molar ratio of the compound represented by the formula (IX) to the compound represented by the formula (VII) or a salt thereof is from 1: 0.5 to 1: 5. The most suitable feed molar ratio of the compound represented by the formula (IX) to the compound represented by the formula (VII) or a salt thereof is from 1: 0.8 to 1: 3.

The compound represented by the formula (VI) is obtained using the compound represented by the formula (X) in the presence of a dehydrating agent. The dehydrating agents include DCC (dicyclohexyl carbodiimide), EDC HCl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), CDI (N, N'-carbonyldiimidazole) and DIC (N, N'-diisopropyl carbodiimide). The molar amount of the dehydrating agent is 0.1 to 10 times that of the compound represented by the formula (X). More suitable molar amount of the dehydrating agent is 0.5 to 5 times the compound represented by the formula (X). The optimum molar amount of the dehydrating agent is 1 to 3 times the compound represented by the formula (X). The reaction temperature is -10 to 120 ℃. More suitable reaction temperature is 0-100 degreeC. The most suitable reaction temperature is 0 to 80 ° C. The reaction was carried out in dichloromethane, chloroform, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N In a solvent such as N-diethylformamide, dimethyl sulfoxide or acetonitrile or mixtures thereof.

A third method for preparing compounds represented by formula (VI) disclosed herein is as follows:

(XI) (XIII)

In the above formula, 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 (XI) are represented by R ¹⁰ , R ¹¹ , Same as the groups represented by R ¹² , R ¹³ , R ²¹ , R ²² and n; U is selected from the group consisting of Cl, Br, I, OTs (p-toluenesulfonate groups) and OMs (methanesulfonate groups); T is selected from the group consisting of F, Cl, Br, OSu, OBt and OAt. R ¹⁰ in the compound represented by the formula ^{(XIII), R 11, R} 12, R 13, R 21, R 22, a group represented by n and U R ^10, from the compound represented by the formula (XI) R ^11, R ^{It is the} same as the group represented by ¹² , R ¹³ , R ²¹ , R ²² , n and U. Formula represented by (X) R ^1, in the compound represented by R ^3, R ^4, R ²⁰ and the group represented by W R ^1, from the compound represented by the formula ^{(VII) R 3, R 4} , R 20 and W Same as the group.

The compound represented by the formula (XIII) is obtained by reacting the compound represented by the formula (VII) or a salt thereof with the compound represented by the formula (XI) in the presence of a base. The base is triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine, N-methylmorpholine, N-methyl piperidine, N-ethyl piperidine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and mixtures thereof. The molar amount of the base is 0.5 to 10 times of the compound represented by the formula (VII) or a salt thereof. More suitable molar amount of the base is 0.8 to 7 times of the compound represented by the formula (VII) or a salt thereof. The most suitable molar amount of the base is 1 to 5 times the compound represented by the formula (VII) or a salt thereof. The reaction was carried out with dichloromethane, chloroform, 1,2-dichloroethane, acetone, ethyl acetate, isopropanol, methyl acetate, propyl acetate, methyl propionate, ethyl propionate, acetonitrile, ethanol, N, N-dimethylformamide , N, N-diethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol, ethanol, propanol, water or It is carried out in the same solvent as a mixture thereof. The reaction temperature is -20 to 120 ℃. More suitable reaction temperature is -10 to 100 ℃. The most suitable reaction temperature is 0 to 80 ° C. The feed molar ratio of the compound represented by formula (VII) or a salt thereof to the compound represented by formula (XI) is from 1: 0.2 to 1:10. A more suitable feed molar ratio of the compound represented by the formula (VII) or a salt thereof to the compound represented by the formula (XI) is from 1: 0.5 to 1: 5. The optimal feed molar ratio of the compound represented by formula (VII) or a salt thereof to the compound represented by formula (XI) is 1: 0.8 to 1: 3.

The compound represented by the formula (VI) is obtained using the compound represented by the formula (XIII) in the presence of a basic reagent. The basic reagents are triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine, N-methylmorpholine , N-methyl piperidine, N-ethyl piperidine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, Lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide and mixtures thereof. The amount of the basic reagent is 0.5 to 3 times the compound represented by the formula (XIII) or a salt thereof. A more suitable amount of the basic reagent is 0.8 to 2 times the compound represented by the formula (XIII) or a salt thereof. The most suitable amount of the basic reagent is 1 to 1.5 times the compound represented by the formula (XIII) or a salt thereof. The reaction was carried out with dichloromethane, chloroform, 1,2-dichloroethane, acetone, ethyl acetate, isopropanol, methyl acetate, propyl acetate, methyl propionate, ethyl propionate, acetonitrile, ethanol, N, N-dimethylformamide , N, N-diethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or mixtures thereof. The reaction temperature is -20 to 120 ℃. More suitable reaction temperature is -10 to 100 ℃. The most suitable reaction temperature is 0 to 80 ° C.

A fourth method for preparing a compound represented by formula (VI) disclosed herein is as follows:

(XIV)

In the compounds represented by the general formula ^{(XIV) R 10, R 11} , R 12, R 13, R 21, R 22 and the group represented by n R ¹⁰ in the compound represented by the formula ^{(III), R 11, R} 12 , R ¹³ , R ²¹ , R ²² and n are the same as the groups represented by.

The compound represented by the formula (VI) is obtained by reacting the compound represented by the formula (XIV) or a salt thereof with the compound represented by the formula (VII) in the presence of an acidic and / or basic reagent, wherein the basic reagent is trimethylamine , Triethylamine, pyridine, N-methylmorpholine, N-methyl piperidine, N-ethyl piperidine, diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and Selected from the group consisting of mixtures thereof. The molar amount of the basic reagent is 0.5 to 10 times the compound represented by the formula (VII) or a salt thereof. More suitable molar amount of the basic reagent is 0.8 to 5 times of the compound represented by the formula (VII) or a salt thereof. The most suitable molar amount of the basic reagent is 1 to 3 times the compound represented by the formula (VII) or a salt thereof. The acidic reagents include hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, methylsulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, citric acid, tartaric acid, lactic acid, malic acid and mixtures thereof. It is selected from the group consisting of. The molar amount of the acidic reagent is 0.05 to 500 times (moles) of the compound represented by the formula (VII). More suitable molar amount of the acidic reagent is 0.2 to 50 times (moles) of the compound represented by the formula (VII). The most suitable molar amount of the acidic reagent is 0.7 to 5 times (moles) of the compound represented by the formula (VII). The reaction is dichloromethane, chloroform, acetone, acetonitrile, ethyl acetate, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, In a solvent such as ethylene glycol monoethyl ether, methyl acetate, propyl acetate, methyl propionate, ethyl propionate, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide or mixtures thereof do. The reaction temperature is -20 to 100 ℃. More suitable reaction temperature is -10 to 80 ℃. The most suitable reaction temperature is 0 to 50 ° C.

A fifth method for preparing compounds represented by formula (VI) disclosed herein is as follows:

(XV) (XVI)

(XVII)

Where

The groups represented by R ¹⁵ and Q in formula (XV) are the same as the groups represented by R ¹⁵ and Q in formula (IV). The groups represented by R ¹⁵ and Q in formula (XVI) are the same as the groups represented by R ¹⁵ and Q in formula (IV). R ^1, in formula ^{(XVI) R 3, R 4} , R 20 and the group represented by W is the same groups represented by ^{R 1, R 3, R 4} , R 20 and W in formula (VII). The groups represented by R ¹⁵ and Q in formula (XVII) are the same as the groups represented by R ¹⁵ and Q in formula (IV). R ^1, in formula ^{(XVII) R 3, R 4} , R 20 and the group represented by W is the same groups represented by ^{R 1, R 3, R 4} , R 20 and W in formula (VII).

The compound represented by formula (XVI) or formula (XVII) is obtained by reacting a compound represented by formula (VII) or a salt thereof with a compound represented by formula (XV). The reaction is dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, methyl propionate, ethyl propionate, 1,2-dichloroethane, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl It is carried out in a solvent such as ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide, acetonitrile, water or mixtures thereof. Pyridine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine or mixtures thereof may optionally be added as catalyst in the reaction. The molar amount of the catalyst is 0.01 to 10 times that of the compound represented by the formula (VII). More suitable molar amount of the catalyst is 0.02 to 5 times the compound represented by the formula (VII). The optimum molar amount of the catalyst is 0.05 to 1 times that of the compound represented by the formula (VII). Triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methyl piperidine, N-ethyl piperidine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (Pyrrolidin-1-yl) pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or mixtures thereof is optionally added as an acid binder in the reaction. can do. The molar amount of the acid binder is 0.4 to 20 times that of the compound represented by the formula (VII). More suitable molar amount of the acid binder is 0.8 to 10 times the compound represented by the formula (VII). The optimum molar amount of the acid binder is 1 to 5 times the compound represented by the formula (VII). The reaction temperature is -20 to 100 ℃. More suitable reaction temperature is -10 to 80 ℃. The optimum reaction temperature is 0 to 80 ° C. The feed molar ratio of the compound represented by formula (VII) or a salt thereof to the compound represented by formula (XV) is from 1: 0.2 to 1:10. More suitable feed molar ratios of the compound represented by formula (VII) or salts thereof to the compound represented by formula (XV) are from 1: 0.5 to 1: 5. The most suitable feed molar ratio of the compound represented by the formula (VII) or a salt thereof to the compound represented by the formula (XV) is 1: 0.8 to 1: 3.

The compound represented by the formula (VI) can be obtained using the compound represented by the formula (XVI) or the formula (XVII) in the presence of a dehydrating agent. The dehydrating agents include DCC (dicyclohexyl carbodiimide), EDC HCl (1-ethyl-3- (3-dimethylamino propyl) carbodiimide hydrochloride), CDI (N, N'-carbonyldiimidazole) and DIC (N, N'-diisopropyl carbodiimide). The molar amount of the dehydrating agent is 0.1 to 10 times that of the compound represented by the formula (XVI) or (XVII). More suitable molar amount of the dehydrating agent is 0.5 to 5 times the compound represented by the formula (XVI) or (XVII). The optimum molar amount of the dehydrating agent is 1 to 3 times the compound represented by the formula (XVI) or (XVII). The reaction temperature is -10 to 120 ℃. More suitable reaction temperature is 0-100 degreeC. Most suitable reaction temperature is 20 to 100 ° C. The reaction was carried out in dichloromethane, chloroform, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N In a solvent such as, N-diethylformamide, dimethyl sulfoxide, acetonitrile or mixtures thereof. Pyridine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine or mixtures thereof can be added as catalyst in the reaction. The molar amount of the catalyst is 0.01 to 1 times the compound represented by the formula (XVI) or (XVII). More suitable molar amount of the catalyst is from 0.02 to 0.8 times the compound represented by the formula (XVI) or (XVII). The optimum molar amount of the catalyst is 0.03 to 0.5 times the compound represented by the formula (XVI) or (XVII).

A sixth method for preparing compounds represented by formula (VI) disclosed herein is as follows:

(XX)

Groups represented by R ^15, X, Y and Q in the compound represented by the formula (XX) are the same groups represented by R ^15, X, Y and Q in the compound represented by the formula (IV). In the compound represented by the formula (XX), U represents Cl, Br, OMs (methanesulfonate group) or OTs (p-toluenesulfonate group).

The compound represented by the formula (IV) can be obtained by reacting the compound represented by the formula (VII) or a salt thereof with the compound represented by the formula (XX) in the presence of a base. The reaction is dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, methyl propionate, ethyl propionate, 1,2-dichloroethane, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl It is carried out in a solvent such as ether, N, N-dimethylformamide, N, N-diethylformamide, dimethyl sulfoxide, acetonitrile, water or mixtures thereof. Pyridine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine or mixtures thereof may optionally be added as catalyst in the reaction. The molar amount of the catalyst is 0.01 to 10 times that of the compound represented by the formula (VII). More suitable molar amount of the catalyst is 0.02 to 5 times the compound represented by the formula (VII). The optimum molar amount of the catalyst is 0.05 to 1 times that of the compound represented by the formula (VII). Bases that can be added in the reaction include, but are not limited to, triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methyl piperidine, N-ethyl piperidine , 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium Hydroxides or mixtures thereof. The molar amount of the base added to the reaction is 0.4 to 20 times the compound represented by the formula (VII). A more suitable molar amount of base added to the reaction is 0.8 to 10 times the compound represented by the formula (VII). The optimum molar amount of base added to the reaction is 1 to 5 times the compound represented by the formula (VII). The reaction temperature is -20 to 100 ℃. More suitable reaction temperature is -10 to 80 ℃. The most suitable reaction temperature is 0 to 80 ° C. The feed molar ratio of the compound represented by the formula (VII) or a salt thereof to the compound represented by the formula (XX) is from 1: 0.2 to 1:10. More suitable feed molar ratios of the compound represented by formula (VII) or salts thereof to the compound represented by formula (XX) are from 1: 0.5 to 1: 5. The most suitable feed molar ratio of the compound represented by the formula (VII) or a salt thereof to the compound represented by the formula (XX) is from 1: 0.8 to 1: 3.

The first method for preparing a compound represented by the formula (I) disclosed in the present invention is as follows:

The compound represented by the formula (I) is a compound represented by the formula (VI) in which R ²⁰ represents OH is represented by R ⁸ COOH, a peptide chain, HOOC-Ar-R ²⁷ , the following formula (IX), Obtained by reaction with a compound represented by formula (XV) or a compound represented by formula (XXI):

     (XXI) (IX) (XV)

Where

From COOH R ⁸ R ⁸ is H or C _1-6 denotes a hydrocarbyl; R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each independently represent H or C _1-6 hydrocarbyl; Ar represents an aromatic ring or an aromatic heterocyclic ring; R ²⁷ is F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbyl, OC _1-6 hydrocarbyl, OC (O) C _1-6 Consisting of hydrocarbyl, C (O) OC _1-6 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl and S (O) ₂ C _1-6 hydrocarbyl 0 to 5 identical or different groups selected from the group. The peptide chain has a free carboxyl group and has 0 to 2 identical or different C _1-6 hydrocarbyl groups or amino protecting groups at the N-terminus, wherein the amino protecting groups are from the group consisting of Fmoc, Boc, CBZ, Tr and Alloc Is selected.

Condensing agents can be added to the reaction. The condensing agent is selected from the group consisting of DCC, EDC HCl, CDI, DIC and mixtures thereof. The molar amount of the condensing agent is 0.1 to 10 times that of the compound represented by the formula (VI). More suitable molar amount of the condensing agent is 0.5 to 5 times the compound represented by the formula (VI). The optimum molar amount of the condensing agent is 1 to 3 times the compound represented by the formula (VI). The reaction temperature is -10 to 120 ℃. More suitable temperatures are from 0 to 100 ° C. The optimum reaction temperature is 20 to 100 ° C. The reaction was carried out in dichloromethane, chloroform, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N In a solvent such as, N-diethylformamide, dimethyl sulfoxide, acetonitrile or mixtures thereof. Pyridine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine or mixtures thereof may optionally be added as catalyst in the reaction. The molar amount of the catalyst is 0.01 to 10 times that of the compound represented by the formula (VI). More suitable molar amount of the catalyst is 0.02 to 5 times the compound represented by the formula (VI). The optimum molar amount of the catalyst is 0.05 to 1 times that of the compound represented by the formula (VI). The feed molar ratio of compound represented by formula (VI) to R ⁸ COOH, peptide chain, HOOC-Ar-R ²⁷ or compound represented by formula (XXI) is from 1: 0.2 to 1:10. A more suitable feed molar ratio of the compound represented by formula (VI) to R ⁸ COOH, peptide chains, HOOC-Ar-R ²⁷ or a compound represented by formula (XXI) is from 1: 0.5 to 1: 7. The optimal feed molar ratio of compound represented by formula (VI) to R ⁸ COOH, peptide chain, HOOC-Ar-R ²⁷ or compound represented by formula (XXI) is from 1: 0.8 to 1: 5. If necessary, base may be added as an acid binder in the reaction. Bases that can be added to the reaction include, but are not limited to, triethylamine, trimethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methyl piperidine, N-ethyl piperidine , 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium Hydroxides or mixtures thereof. The molar amount of the base added to the reaction is 0.4 to 20 times the compound represented by the formula (VI). A more suitable molar amount of base added to the reaction is 0.8 to 10 times the compound represented by the formula (VI). The optimum molar amount of base added to the reaction is 1 to 5 times the compound represented by the formula (VI).

Through the conventional deprotection reaction used by those skilled in the art, the target compound is prepared from the product obtained by reacting the compound represented by the formula (VI) with a peptide chain having an N-terminus protecting group. That is, Fmoc can be deprotected using NH ₃ , aminoethanol, dimethylamine, diethylamine, piperidine, piperazine or DBU; Boc or Tr can be deprotected using hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, trifluoroacetic acid, methylsulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid or hydrogen chloride gas.

A second method for preparing a compound represented by formula (I) disclosed herein is as follows:

The compound represented by formula (I), R ²⁰ is a compound represented by the formula (VI) represents an OH, R ⁸ is obtained by reaction with R ⁸ NCO represents a C _1-6 hydrocarbyl. The feed ratio of compound represented by formula (VI) to R ⁸ NCO is from 1: 0.5 to 1: 5. A more suitable feed ratio of compound represented by formula (VI) to R ⁸ NCO is 1: 0.7 to 1: 2. The optimum feed ratio of compound represented by formula (VI) to R ⁸ NCO is 1: 0.8 to 1: 1.5.

Trimethylamine, triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methyl piperidine, N-ethyl piperidine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- Tertiary amines such as (pyrrolidin-1-yl) pyridine or mixtures thereof can be added to the reaction. The added molar amount of the tertiary amine is 0.5 to 10 times the compound represented by the formula (VI). A further suitable molar amount of the tertiary amine is 0.5 to 7 times that of the compound represented by the formula (VI). The optimum addition molar amount of the tertiary amine is 0.5 to 3 times that of the compound represented by the formula (VI). 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine or mixtures thereof may optionally be added as catalyst in the reaction. The added molar amount of the catalyst is 0.01 to 1 times the compound represented by the formula (VI). A further suitable molar amount of the catalyst is 0.02 to 0.8 times that of the compound represented by the formula (VI). The optimum molar amount of the catalyst is 0.05 to 0.3 times that of the compound represented by the formula (VI). The reaction temperature is -10 to 120 ℃. More suitable reaction temperature is 0-100 degreeC. Most suitable reaction temperature is 20 to 100 ° C. The reaction was carried out in dichloromethane, chloroform, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N In a solvent such as, N-diethylformamide, dimethyl sulfoxide, acetonitrile or mixtures thereof.

A third method for preparing compounds represented by formula (I) disclosed herein is as follows:

The compound represented by the formula (I) can be obtained by reacting a compound represented by the formula (VI) in which R ²⁰ represents OH with phosgene, diphosgene or triphosgene, and then adding HNR ⁸ R ⁹ . The feed molar ratio of the compound represented by the formula (VI) to phosgene, diphosgene or triphosgene is from 1: 0.5 to 1: 5. A more suitable feed molar ratio of the compound represented by the formula (VI) to phosgene, diphosgene or triphosgene is from 1: 0.7 to 1: 3. The optimal feed molar ratio of compound represented by the formula (VI) to phosgene, diphosgene or triphosgene is from 1: 0.9 to 1: 2. The feed molar ratio of compound represented by formula (VI) to HNR ⁸ R ⁹ is from 1: 0.5 to 1: 5. A more suitable feed molar ratio of compound represented by formula (VI) to HNR ⁸ R ⁹ is from 1: 0.7 to 1: 3. The optimum feed molar ratio of compound represented by formula (VI) to HNR ⁸ R ⁹ is from 1: 0.9 to 1: 2.

Tertiary amines such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, trimethylamine, triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, N-methyl piperidine, Acid binders such as N-ethyl piperidine, 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine or mixtures thereof can be added to the reaction. The added molar amount of the acid binder is 1 to 20 times the compound represented by the formula (VI). A further suitable molar amount of the acid binder is 1.5 to 15 times the compound represented by the formula (VI). The optimal addition molar amount of the acid binder is 2 to 10 times the compound represented by the formula (VI). 4-dimethylamino pyridine, 4-diethylamino pyridine, 4- (pyrrolidin-1-yl) pyridine or mixtures thereof may optionally be added as catalyst in the reaction. The added molar amount of the catalyst is 0.01 to 1 times the compound represented by the formula (VI). A further suitable molar amount of the catalyst is 0.02 to 0.8 times that of the compound represented by the formula (VI). The optimum molar amount of the catalyst is 0.05 to 0.3 times that of the compound represented by the formula (VI). The reaction temperature is -100 to 120 ℃. More suitable reaction temperature is -78 to 100 ° C. The most suitable reaction temperature is -78 to 80 ° C. The reaction was carried out in dichloromethane, chloroform, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N, N-dimethylformamide, N In a solvent such as, N-diethylformamide, dimethyl sulfoxide, acetonitrile or mixtures thereof.

The compound represented by formula (I) can be used to prepare a medicament for the treatment of cancer or a tumor. Examples of the cancer include, but are not limited to, intestinal cancer, liver cancer, stomach cancer, breast cancer, lung cancer, kidney cancer, cervical cancer, pancreatic cancer, ovarian cancer, prostate cancer, cerebral glioma, lymphoma, skin cancer, melanoma, head and neck cancer, thyroid cancer, Multiple myeloid cancer and leukemia.

Drugs for the treatment of cancer or tumors prepared from the compound represented by the formula (I) include taxol anticancer agents, camptothecins anticancer agents, vinblastine anticancer agents, cyclophosphamide, 5-fluorouracil, thalidomide, It can be used in combination with other suitable anticancer agents, immunopotentiators, anticancer synergists, hormonal agents or traditional herbal medicines such as cisplatin, Revlimid, tacreva, irresa, glibeck and mixtures thereof. When used in combination with other therapeutic agents, the agents may be administered simultaneously or sequentially.

Dosage formulations of a medicament for the treatment of cancer or tumors prepared from a compound represented by formula (I) depend on the route of administration such as gastrointestinal administration, intravenous infusion, intraperitoneal administration, intradermal administration, intramuscular administration, intranasal administration or topical administration. . Dosage formulations comprising at least one compound represented by formula (I) further comprise suitable carriers, fillers, solvents, diluents, colorants and / or tackifiers necessary to prepare the dosage form.

Dosage formulations of a medicament for the treatment of cancer or tumors prepared from a compound represented by formula (I) are preferably, but not limited to, injection formulations including powder injections, lyophilized powder injections, aqueous solution injections, emulsions and suspensions to be.

Abbreviation: Su: succinimido; Bt: benzotriazol-1-yl; At: 7-azabenzotriazol-1-yl; Fmoc: (9H-fluorene-9-ylmethoxy) carbonyl; Boc: tert-butoxycarbonyl; CBZ: benzyloxycarbonyl; Tr: trimethylphenyl; Alloc: allyloxycarbonyl; DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene.

Specific embodiment

Example 1 3′-pyrroleyldoxorubicin

Into a 1 L three-necked flask was charged 3.076 g of doxorubicin hydrochloride, 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 mixture was heated to reflux under an argon atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was poured into 200 ml of ice water. The mixture was left to separate. The organic phase was washed once with 200 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and rotary evaporated. While stirring with an ice bath, 100 ml of 5% aqueous sodium bicarbonate solution was added to the aqueous phase. The mixture was extracted with chloroform (50 ml × 3) and the chloroform layers combined. The combined chloroform layers were washed once with 100 ml of saturated sodium chloride solution. The mixture was filtered and rotary evaporated to remove the solvent. The resulting crude product was combined with the crude product. The combined products were purified by column chromatography and eluted with a solvent of chloroform: methanol = 35: 1. 2.91 g of the product were obtained. MS: 592 (M-1).

The compounds of Examples 2-6 were prepared in the same manner as described in Example 1.

Example 2: 3'-pyrrolyyl-5-iminodaunomycin, MS: 576 (M-1).

Example 3: 3'-pyrrolyyl-idarubicin, MS: 547 (M-1).

Example 4: 3'-pyrroylyl-isorubicin, MS: 577 (M-1).

Example 5: 3'-pyrroleyldoxorubicin, MS: 577 (M-1).

Example 6: 3'-pyrrolyyl-4 '-(pyran-2-yl) doxorubicin, MS: 677 (M-1).

Example 7: 3′-succinimidodoxorubicin

100 mg of doxorubicin hydrochloride was placed in a 50 ml single sphere round bottom bottle and dissolved in 3 ml of DMF. 63 μl of DIEA (diisopropyl ethyl amine) and 2 mg of DMAP (4-dimethylamino pyridine) were added and stirred for 10 minutes. 21 mg of succinic anhydride was added and stirred for 1 h under argon atmosphere. The reaction solution was rotary evaporated. 20 mg of distilled water and 10 ml of chloroform were added to the reaction residue and the mixture was pumped and filtered to give a filter cake. The filter cake was vacuum dried. 18 mg of the filter cake was transferred to a 50 ml single-neck flask. To the single-neck flask, 5 ml of dichloromethane (dried molecularly) and 12 μl triethylamine (dried molecularly) were added followed by 69 mg of cyanuric chloride. The mixture was stirred at room temperature. 20 ml of dichloromethane was added to the reaction solution. The mixture was washed once with 20 ml of water. The resulting organic phase was washed once with 20 ml of saturated sodium chloride solution. The solution was rotary evaporated to remove the solvent. A crude product was obtained. The crude product was purified by thin layer chromatography and developed with chloroform: methanol = 22: 1. The title compound was obtained. MS: 624 (M-1).

The compounds of Examples 8-11 were prepared in the same manner as described in Example 7:

Example 8: 3′-glutarimidodoxorubicin, MS: 1296 (2M + H ₂ O)

Example 9: 3'-maleimidodoxorubicin, MS: 623 (M).

Example 10: 3 '-(pyrido- (2,3) succinimido) doxorubicin, MS: 722 (M + EtOH).

Example 11: 3 ′-(benzo- (2,3) succinimido) doxorubicin, MS: 1345 (2M).

Example 12 3'-Butyrolactam Toxorubicin

10 mg of doxorubicin hydrochloride was dissolved in 5 ml of DMF (anhydrous). The temperature was lowered to 0-5 ° C with ice bath. 7 mg of diisopropylethylamine were added and stirred for 10 minutes. 2.4 mg of 4-chlorobutyryl chloride was added and the reaction was carried out for 30 minutes. 100 ml of water were added to the ice bath. The mixture was extracted three times with chloroform (50 ml × 3) and the chloroform layers were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and rotary evaporated to remove the solvent. The crude product was purified by thin layer chromatography and developed with chloroform: methanol = 95: 5. 8 mg of product were obtained and then the product was dissolved in 3 ml of DMF (anhydrous). Under argon atmosphere, the temperature was lowered to -5-0 ° C with ice bath. 0.3 mg sodium hydride was added and the mixture was stirred for 24 hours. After the reaction was completed, 50 ml of water were added. The resulting mixture was extracted three times with chloroform (50 ml × 3) and the chloroform layers were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and rotary evaporated to remove the solvent. The crude product was purified by thin layer chromatography and developed with chloroform: methanol = 30: 1. 6 mg of product was obtained. MS: 611.

Example 13: 3′-pyrroleyldoxorubicin-14-oxo-hydrogen succinate

845 mg of 3'-pyrroleyldoxorubicin was placed in a 50 ml single-necked flask and dissolved in 20 ml of chloroform. The temperature was lowered to -10 ° C under argon atmosphere. 704 mg of DMAP and 570 mg of succinic anhydride were added. The mixture was stirred overnight. After the reaction was completed, 300 ml of chloroform was added to the reaction solution. The mixture was washed once with 100 ml of 5% aqueous citric acid solution and once with 100 ml of saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and rotary evaporated. A crude product was obtained. The crude product was purified by column chromatography and eluted with chloroform: methanol: glacial acetic acid = 475: 25: 5. 238 mg of product were obtained. MS: 692 (M-1).

The compounds of Examples 14-25 were prepared in the same manner as described in Example 13:

Example 14 3′-Pyrroylyl-Esorubicin-14-oxo-hydrogen succinate, MS: 676 (M-1).

Example 15: 3'-pyrrolyyl-4 '-(pyran-2-yl) doxorubicin-14-oxo-hydrogen succinate, MS: 776 (M-1).

Example 16: 3'-succinimidodoxorubicin-14-oxo-hydrogen succinate, MS: 724 (M-1).

Example 17: 3'-glutarimidodoxorubicin-14-oxo-hydrogen succinate, MS: 738 (M-1).

Example 18: 3'-maleimidodoxorubicin-14-oxo-hydrogen succinate, MS: 722 (M-1).

Example 19: 3 '-(pyrido- (2,3) succinimido) doxorubicin-14-oxo-hydrogen succinate, MS: 773 (M-1).

Example 20: 3 '-(benzo- (2,3) succinimido) doxorubicin-14-oxo-hydrogen succinate, MS: 772 (M-1).

Example 21: 3'-pyrrolyyldoxorubicin-14,4'-oxo-hydrogen disuccinate, MS: 792 (M-1).

Example 22: 3'-pyrroleyldoxorubicin-14-oxo-hydrogen maleate, MS: 690 (M-1).

Example 23 3'-pyrroleyldoxorubicin-14,4'-oxo-hydrogen dimaleate, MS: 788 (M-1).

Example 24 3′-pyrroleyldoxorubicin-14-oxo-hydrogen glutarate, MS: 730 (M + Na).

Example 25 3'-pyrroleyldoxorubicin-14,4'-oxo-hydrogen diglutartate, MS: 820 (M-1).

Example 26 3'-pyrroleyldoxorubicin-14-oxo- (3-nitro-2-carboxyl) benzoate

50 mg of 3'-pyrroleyldoxorubicin was placed in a 50 ml single-neck flask and dissolved in 2.5 ml of chloroform. The temperature was lowered to -5 ° C under argon atmosphere. 42 mg DMAP and 65 mg 3-nitrophthalic anhydride were added. The mixture was stirred overnight. After the reaction was completed, 150 ml of chloroform was added to the reaction solution. The mixture was washed once with 100 ml of 5% aqueous citric acid solution. The organic phase was washed once with 100 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and rotary evaporated. Purification by thin layer chromatography and development with chloroform: methanol: glacial acetic acid = 450: 50: 5 gave the title product. MS: 785 (M-1).

The compounds of Examples 27-37 were prepared in the same manner as described in Example 26:

Example 27: 3'-pyrroleyldoxorubicin-14-oxo- (3-fluoro-2-carboxyl) benzoate, MS: 758 (M-1).

Example 28: 3'-pyrroleyldoxorubicin-14,4'-oxo-bis (3-fluoro-2-carboxyl) benzoate, MS: 925.

Example 29: 3'-pyrrolyyldoxorubicin-14-oxo- (2-carboxy-6-fluoro) benzoate, MS: 758 (M-1).

Example 30: 3'-pyrroleyldoxorubicin-14,4'-oxo-bis (6-fluoro-2-carboxyl) benzoate, MS: 925.

Example 31: 3'-pyrrolyyldoxorubicin-14-oxo- (3,4,5,6-tetrafluoro-2-carboxy) benzoate, MS: 812 (M-1).

Example 32: 3'-pyrrolyyldoxorubicin-14,4'-oxo-bis (3,4,5,6-tetrafluoro-2-carboxyl) benzoate, MS: 1033 (M).

Example 33: 3'-pyrrolyyldoxorubicin-14-oxo- (2,4-dicarboxyl) benzoate, MS: 784 (M-1).

Example 34: 3'-pyrrolyyldoxorubicin-14,4'-oxo-bis (2,4-dicarboxyl) benzoate, MS: 978 (M).

Example 35: 3'-pyrrolyyldoxorubicin-14,4'-oxo-bis (2-carboxyl) benzoate, MS: 889 (M).

Example 36: 3'-pyrrolyyldoxorubicin-14-oxo- (3-carboxyl) pyridine-2-formate, MS: 741 (M-1).

Example 37: 3'-pyrroleyldoxorubicin-14,4'-oxo- (3-nitro-2-carboxyl) dibenzoate, MS: 978 (M-1).

Example 38 3'-Pyrroyldoxorubicin-14-oxo-alanineate hydrochloride

59.3 mg of 3'-pyrroleyldoxorubicin and 10 ml of dichloromethane (dried to molecular sieve) were placed in a 50 ml single-necked flask and stirred under an argon atmosphere. 63 mg Boc-alanine, 38 mg EDC HCl and 12 mg DMAP were added. After the reaction was completed, 50 ml of dichloromethane were added. The mixture was washed once with 100 ml of water. The aqueous phase was back extracted once with dichloromethane and combined with the organic phase. The resulting phase was washed once with 100 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and rotary evaporated. Purification by thin layer chromatography and development with chloroform: methanol = 35: 1 gave 43 mg of product. The resulting compound was dissolved in 1 ml tetrahydrofuran (re-evaporated) and injected with argon gas. The temperature was lowered to -5 ° C. Hydrogen chloride solution in 1 ml diethyl ether was added. The mixture was stirred for 2 hours and then filtered. The filter cake was eluted three times with diethyl ether to afford the title compound. MS: 665 (M + 1).

The compounds of Examples 39-53 were prepared in the same manner as described in Example 38:

Example 39: 3'-pyrrolyyldoxorubicin-14-oxo-valinate hydrochloride, MS: 693 (M + 1).

Example 40: 3'-pyrrolyyldoxorubicin-14-oxo-glycinate hydrochloride, MS: 651 (M + 1).

Example 41: 3'-pyrrolyyldoxorubicin-14-oxo-leucineate hydrochloride, MS: 707 (M + 1).

Example 42: 3'-pyrrolyyldoxorubicin-14-oxo- (2,2-dimethyl) glycinate hydrochloride, MS: 679 (M + 1).

Example 43: 3'-pyrrolyyldoxorubicin-14-oxo- (2-phenyl) glycinate hydrochloride, MS: 727 (M + 1).

Example 44: 3'-pyrroleyldoxorubicin-14-oxo-2-diethylaminoacetate, MS: 707 (M + 1).

Example 45: 3'-pyrroleyldoxorubicin-14-oxo-2-morpholinyl acetate, MS: 720 (M + 1).

Example 46: 3'-pyrrolyyldoxorubicin-14-oxo- (N-glycyl) valinate hydrochloride, MS: 750 (M + 1).

Example 47: 3'-pyrrolyyl-esorubicin-14-oxo-glycinate hydrochloride, MS: 635 (M + 1).

Example 48: 3'-pyrrolyyl-4 '-(pyran-2-yl) doxorubicin-14-oxo-glycinate hydrochloride, MS: 735 (M + 1).

Example 49: 3'-succinimidodoxorubicin-14-oxo-glycinate hydrochloride, MS: 683 (M + 1).

Example 50: 3'-glutarimidodoxorubicin-14-oxo-glycinate hydrochloride, MS: 697 (M + 1).

Example 51, 3'-maleimidodoxorubicin-14-oxo-glycinate hydrochloride, MS: 681 (M + 1).

Example 52: 3 '-(pyrido- (2,3) succinimido) doxorubicin-14-oxo-glycinate hydrochloride, MS: 732 (M + 1).

Example 53: 3 '-(Benzo- (2,3) succinimido) doxorubicin-14-oxo-glycinate hydrochloride, MS: 731 (M + 1).

Example 54: 3'-pyrrolyyldoxorubicin-14-oxo-β-alanine hydrochloride, MS: 697 (M + 1).

Cytotoxicity Assay (MTS Assay)

I. 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 1640 culture; MTT: blue tetrazolium; DMSO: dimethyl sulfoxide; 96-well cell culture plates;

Anticancer compound (manufactured by Tianjin Hemei Bio-Tech Co., Ltd.);

Positive control drug: doxorubicin (manufactured by Zhejiang Hyshun Pharmaceutical Co., Ltd.).

II. Cell growth inhibitory activity measurement

1. Cell Culture and Drug Treatment:

Cells were seeded in RPMI 1640 cell culture containing 10% fetal bovine serum (supplemented with 100 ku / L penicillin and 100 ku / L streptomycin). The culture dish was placed in a cell incubator containing 5% C0 ₂ at 37 ° C. The culture was changed every 2-3 days. Cells were digested with 0.25% trypsin solution and passed through to collect.

Cells in logarithmic growth phase were prepared as cell suspensions with desired concentrations using RPMI 1640 cell culture containing 10% fetal calf serum. The cell suspension was added on 96 well cell culture plates at 3000-5000 (100 μl) per well. After incubation for 24 hours, 100 μl of test material with different concentrations were added per well. These plates were placed with four parallel wells for each concentration. After incubation for 72 to 120 hours, the supernatant was discarded. 100 μl of freshly formulated 0.5 mg / ml MTT serum-free culture was added to each well. After incubation at 37 ° C. for 4 hours, the supernatant was discarded. Formazan was dissolved in 200 μl DMSO. After shaking gently for 15 minutes, the absorbance values (OD values) at the detection wavelength of 570 nm and the reference wavelength of 450 nm were measured using the enzyme labeling method.

2. Data Processing

Data is expressed as x ± s. Inhibition rate = (OD value of control-OD value of control) / OD value of control × 100%. The anti-cancer effect was shown with the maximum inhibition rate I _max and half the effect concentration (IC ₅₀ ). The drawings were drawn with MicroCal Origin software. The inhibition curve of the test substance for the growth of cancer cells was prepared by the Four Parameters Logistic Program of the software. Half effect concentrations (IC ₅₀ : μg / ml) that inhibit the proliferation of cancer cells were calculated.

3. Results

Treatment concentrations of the test substance were 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 And 20 μg / ml. Treatment concentrations of doxorubicin (positive drug) were 1.25 µg / ml, 5 µg / ml, and 20 µg / ml. On 96-well plates, 3000-5000 cells were seeded in each well to place 4 parallel wells for each concentration. Table 1 shows the growth inhibition of the compound against Lovo cells at a concentration of 1 μM. Table 2 shows the inhibitory activity of the compounds against various cancer cells. Table 3 shows the inhibition rate of the compound against hyperproliferation of MCF-7 human breast cancer cells at various concentrations.

Growth inhibition of compounds against Lovo cells at a concentration of 1 μM compound Growth inhibition rate (%) compound Growth inhibition rate (%) Doxorubicin 50.35 Example 5 67.25 Example 1 80.62 Example 6 90.94 Example 2 74.0 Example 7 83.31 Example 3 88.9 Example 13 76.05 Example 4 40.71 Example 38 78.44

Inhibitory Activity of Compounds Against Cancer Cells compound Half-inhibitory concentration of cell growth (EC ₅₀ ) (μM) MCF-7 cells HCT-8 cells HEPG-2 A549 cell Doxorubicin 1.2 0.9 2.0 0.66 Example 1 0.21 0.49 0.81 0.061 Example 13 0.93 1.87 0.15 2.36 Example 38 0.87 0.59 1.06 0.23

Inhibitory Effect of the Compound of Example 1 on Hyperproliferation of MCF-7 Human Breast Cancer Cells Compound concentration
(占 퐂 / ml) A570 nm-OD value % Inhibition Main parameter 0 1.701 ± 0.161 IC ₅₀ = 0.06023 ± 0.01528 μg / ml


I _max = 83.03% 0.001 1.629 ± 0.257 4.27 0.003 1.744 ± 0.176 -2.49 0.009 1.443 ± 0.079 15.17 0.027 1.238 ± 0.072 27.22 0.082 0.883 ± 0.041 48.09 0.247 0.703 ± 0.058 58.68 0.741 0.461 ± 0.026 72.89 2.222 0.302 ± 0.030 82.26 6.667 0.320 ± 0.030 81.18 20 0.289 ± 0.019 83.03

The activity of the test substance was equal to or slightly better than that of doxorubicin. In addition, the test compounds showed better growth inhibitory effects against various human cancer cell lines such as human colon cancer LOVO cell line, human breast cancer MCF-7 cell line, colon cancer HCT-8 cell line, liver cancer HEPG-2 cell line, and lung cancer A549 cell line.

Experimental Example 1 In vivo MTD Test Recording in Mice

Experimental purpose: Preliminary investigation of the in vivo toxicity of the compound of Example 1 in mice

Experimental Animals: 20 ± 2 g Kunming white mice, purchased from an animal source from the Institute of Radiation Medicine, Chinese Academy of Medical Sciences. Animal License Number: SCXK (JIN) 2005-0001.

Experimental Drugs: Compounds of Example 1

Preparation of Drug Solution: The drug was vortexed to dissolve with 0.5% (V / V) DMSO and then 5% (V / V) of RH40 (ethoxylated hydrogenated castor oil) was added. After mixing with vortex, the volume was measured with normal physiological saline.

Experimental plan:

(1) Single dose: Nine healthy Kunming male white mice weighing 20 ± 2 g were divided into three groups: two belonging to the control; 6 animals belonging to a 20 mg / kg dose; One per 30 mg / kg dose. 20 mg / kg and 30 mg / kg of the compound of Example 1 were administered at a time by tail vein injection to the mice in the administration. The same volume of solvent was administered to the control mice as a control. After administration, health conditions such as mouse behavior, reflex behavior, and motor activity were observed within 1 hour. The body weights of the mice were then recorded daily. Observations were made for 14 days after drug withdrawal and mice were dissected to see if their major organs had noticeable abnormalities.

(2) Multiple dosing: Twelve healthy Kunming white mice, including six male mice and six female mice, weighing 20 ± 2 g, were divided into two groups: one mouse belonging to the control group. ; Five mice belonging to a 10 mg / kg dose. 10 mg / kg of test drug was administered once every three days by tail vein injection to mice in the doses. The same volume of solvent was administered to the control mice as a control. Five mice were administered to each group. After each administration, health conditions such as mouse behavior, reflex behavior and motor activity were observed within 1 hour. The body weights of the mice were recorded daily. After a week of drug withdrawal, normal feeding was performed, and mice were dissected to observe whether their main organs had noticeable abnormalities.

Experiment result:

1. Mortality rate:

(1) Single dose: No death was found.

(2) Multiple dosing: No death was found.

2. Weight change:

(1) Single Dose: The weight of each mouse increased after dosing, and no visible abnormality was observed on the body surface.

(2) Multiple Administration: The weight of each mouse increased slowly after administration, and no visible abnormality was observed on the body surface.

conclusion:

The maximum tolerated dose (MTD) of the test compound was at least 5 times higher than that of doxorubicin (MTD: 8-12 mg / kg).

Claims (20)

A compound represented by the following formula (I) or a salt thereof:

(I)
In this formula,
R ¹ represents H, C _1-4 hydrocarbyl or OC _1-4 hydrocarbyl;
R ² represents H or OR ⁶ , where R ⁶ represents 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 hydrocarbylidene) COOH and a group represented by the following formula (II);

(II)
R ⁸ and R ⁹ each independently represent H or C _1-6 hydrocarbyl, or NR ⁸ R ⁹ is pyrrolidin-1-yl, piperidin-1-yl or morpholin-1-yl Represents; Ar represents an aromatic ring or an aromatic heterocyclic ring; R ²⁷ is F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbyl, OC _1-6 hydrocarbyl, OC (O) C _1-6 Consisting of hydrocarbyl, C (O) OC _1-6 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl and S (O) ₂ C _1-6 hydrocarbyl 0-5 identical or different groups selected from the group; The peptide chain represents a single natural amino acid, a single artificial amino acid or a peptide chain consisting of 2 to 4 natural amino acids, 2 to 4 artificial amino acids, or 2 to 4 natural and artificial amino acids;
W represents O or NH;
R ³ represents H, F, OC _1-4 hydrocarbyl or C _1-4 hydrocarbyl;
R ⁴ represents H, F, C _1-4 hydrocarbyl or OR ⁷ , wherein R ⁷ represents H, 2-pyranyl or R ⁶ ;
R ⁵ represents formula (III), formula (IV), formula (V) or maleimido,

(III) (IV) (V),
In this formula,
n represents 1 or 2;
X is C = O and Y is C = O or CR ²¹ R ²² , or
X is CR ²¹ R ²² and Y represents C═O;
Q represents CH or N;
R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are each independently H, F, Cl, CN, NO ₂ , NH ₂ , OH, C (O) OC _1-4 hydrocarbyl, OC (O) C _1-4 hydrocarbyl, OC _1-4 hydrocarbyl, C _1-4 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl, S (O ) ₂ C _1-6 hydrocarbyl, (C _0-4 hydrocarbylidene) Ar-R ²⁷ and NR ⁸ R ⁹ ;
R ²¹ and R ²² each independently represent H or C _1-4 hydrocarbyl. The compound of formula (I) or a salt thereof according to claim 1, wherein R ¹ represents H, OH or OCH ₃ . The compound of formula (I) or a salt thereof, according to claim 1, wherein W represents O. 3. The compound of claim 1, wherein R ² is H, OH, a hydrogen succinate group, a hydrogen glutarate group, a hydrogen maleate group, a (3-nitro-2-carboxy) benzoate group, (3-fluoro Ro-2-carboxyl) benzoate group, (2-carboxyl-6-fluoro) benzoate group, (3,4,5,6-tetrafluoro-2-carboxyl) benzoate group, (2 , 4-dicarboxyl) benzoate group, (2-carboxyl) benzoate group, (3-carboxyl) pyridine-2-formate group, alanate group, balineate group, glycinate group, leucine With a nate group, a (2,2-dimethyl) glycinate group, a (2-phenyl) glycinate group, a 2-diethylaminoacetate group, a 2-morpholinyl acetate group and a (N-glycyl) valinate group A compound of formula (I) or a salt thereof selected from the group consisting of: The compound of formula (I) or a salt thereof according to claim 1, wherein R ³ represents H or CH ₃ . The compound of claim 1, wherein R ⁴ is H, F, OH, OCH ₃ , 2-pyranyl, hydrogen succinate group, (3-nitro-2-carboxyl) benzoate group, (2-carboxyl) benzo Eate group, (2,4-dicarboxyl) benzoate group, (3,4,5,6-tetrafluoro-2-carboxy) benzoate group, (2-carboxy-6-fluoro) benzo A compound of formula (I) or a salt thereof, selected from the group consisting of an ate group and a (3-fluoro-2-carboxyl) benzoate group. The compound of claim 1, wherein R ⁵ consists of pyrrole-1-yl, succinimido, glutarimido, butyrolactam-1-yl, valerolactam-1-yl, phthalimido and pyridinedicarboxymido Compounds of formula (I) or salts thereof selected from the group. The compound of formula (I) or a salt thereof according to claim 1, wherein the compound represented by formula (I) is selected from the group consisting of:
3'-pyrroleyldoxorubicin,
3′-pyrroleyl-5-iminodaunomycin,
3'-pyrrolyyl-idarubicin,
3'-pyrrolyl-esorubicin,
3'-pyrroleyldoxorubicin,
3'-pyrrolyyl-4 '-(pyran-2-yl) doxorubicin,
3'-succinimidodoxorubicin,
3'-glutarimidodoxorubicin,
3'-maleimidodoxorubicin,
3 '-(pyrido- (2,3) succinimido) doxorubicin,
3 '-(benzo- (2,3) succinimido) doxorubicin,
3'-butyrolactam toxorubicin,
3'-pyrrolyl-esorubicin-14-oxo-hydrogen succinate,
3'-pyrrolyyl-4 '-(pyran-2-yl) doxorubicin-14-oxo-hydrogen succinate,
3'-succinimidodoxorubicin-14-oxo-hydrogen succinate,
3'-glutarimidodoxorubicin-14-oxo-hydrogen succinate,
3'-maleimidodoxorubicin-14-oxo-hydrogen succinate,
3 '-(pyrido- (2,3) succinimido) doxorubicin-14-oxo-hydrogen succinate,
3 '-(benzo- (2,3) succinimido) doxorubicin-14-oxo-hydrogen succinate,
3'-pyrroleyldoxorubicin-14,4'-oxo-hydrogen disuccinate,
3′-pyrroleyldoxorubicin-14-oxo-hydrogen maleate,
3'-pyrroleyldoxorubicin-14,4'-oxo-hydrogen dimaleate,
3'-pyrroleyldoxorubicin-14-oxo-hydrogen glutarate,
3'-pyrroleyldoxorubicin-14,4'-oxo-hydrogen diglutartate,
3'-pyrroleyldoxorubicin-14-oxo- (3-nitro-2-carboxy) benzoate,
3'-pyrrolyyldoxorubicin-14-oxo- (3-fluoro-2-carboxyl) benzoate,
3'-pyrrolyyldoxorubicin-14,4'-oxo-bis (3-fluoro-2-carboxyl) benzoate,
3'-pyrroleyldoxorubicin-14-oxo- (2-carboxy-6-fluoro) benzoate,
3'-pyrroylyldoxorubicin-14,4'-oxo-bis (6-fluoro-2-carboxyl) benzoate,
3'-pyrrolyyldoxorubicin-14-oxo- (3,4,5,6-tetrafluoro-2-carboxy) benzoate,
3'-pyrroylyldoxorubicin-14,4'-oxo-bis (3,4,5,6-tetrafluoro-2-carboxy) benzoate,
3'-pyrrolyyldoxorubicin-14-oxo- (2,4-dicarboxyl) benzoate,
3'-pyrroleyldoxorubicin-14,4'-oxo-bis (2,4-dicarboxyl) benzoate,
3'-pyrroleyldoxorubicin-14,4'-oxo-bis (2-carboxyl) benzoate,
3′-pyrrolyyldoxorubicin-14-oxo- (3-carboxyl) pyridine-2-formate,
3'-pyrroleyldoxorubicin-14,4'-oxo- (3-nitro-2-carboxyl) dibenzoate,
3'-pyrroleyldoxorubicin-14-oxo-alanineate hydrochloride,
3'-pyrroleyldoxorubicin-14-oxo-valinate hydrochloride,
3'-pyrroleyldoxorubicin-14-oxo-glycinate hydrochloride,
3'-pyrroleyldoxorubicin-14-oxo-leucineate hydrochloride,
3'-pyrroleyldoxorubicin-14-oxo- (2,2-dimethyl) glycinate hydrochloride,
3'-pyrroleyldoxorubicin-14-oxo- (2-phenyl) glycinate hydrochloride,
3'-pyrroleyldoxorubicin-14-oxo-2-diethylaminoacetate,
3'-pyrroleyldoxorubicin-14-oxo-2-morpholinyl acetate,
3'-pyrroleyldoxorubicin-14-oxo- (N-glycyl) valinate hydrochloride,
3'-pyrroylyl-isorubicin-14-oxo-glycinate hydrochloride,
3'-pyrrolyyl-4 '-(pyran-2-yl) doxorubicin-14-oxo-glycinate hydrochloride,
3'-succinimidodoxorubicin-14-oxo-glycinate hydrochloride,
3'-glutarimidodoxorubicin-14-oxo-glycinate hydrochloride,
3'-maleimido doxorubicin-14-oxo-glycinate hydrochloride,
3 '-(pyrido- (2,3) succinimido) doxorubicin-14-oxo-glycinate hydrochloride,
3 '-(benzo- (2,3) succinimido) doxorubicin-14-oxo-glycinate hydrochloride, and
3′-Pyrroyldoxorubicin-14-oxo-β-alanine hydrochloride. A process for preparing a compound represented by formula (I) of claim 1 comprising the following steps:
i) reacting a compound represented by formula (VII) or a salt thereof with a compound represented by formula (VIII) in the presence of an acidic, basic, or acidic and basic reagent to obtain a compound represented by formula (VI) step;

(VII)

(VI) (VIII)

The groups represented by R ¹ , R ³ , R ⁴ and W in the compound represented by the formula (VII) are the same as the groups 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; The general formula for the compounds represented by ^{(VI) R 1, R 3} , R 4, R 5 and W groups R ^1, from the compound represented by the first term (I) represented by R ^3, R ^4, R ⁵ and W Same as the group represented by, 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) in claim 1, and R ²¹ and R ²² are each independently H or C _{1- 4} represents hydrocarbyl; And
ii) the compound represented by the formula (VI) wherein R ²⁰ represents OH is represented by R ⁸ COOH, a peptide chain, HOOC-Ar-R ²⁷ , a compound represented by the following formula (IX), a compound represented by the following formula (XV) Reacting with a compound represented by formula (XXI) or R ⁸ NCO to obtain a compound represented by formula (I);

(XXI) (IX) (XV)
In this formula,
In R ⁸ COOH R ⁸ is C _1-6 denotes a hydrocarbyl; R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each independently represent H or C _1-6 hydrocarbyl; Ar represents an aromatic ring or an aromatic heterocyclic ring; R ²⁷ is F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbyl, OC _1-6 hydrocarbyl, OC (O) C _1-6 Consisting of hydrocarbyl, C (O) OC _1-6 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl and S (O) ₂ C _1-6 hydrocarbyl 0-5 identical or different groups selected from the group, wherein the peptide chain has a free carboxyl group and the N-terminus has 0-2 identical or different C _1-6 hydrocarbyl groups or has an amino protecting group, said amino protecting group Is selected from the group consisting of Fmoc, Boc, CBZ, Tr and Alloc;
or
i-1) reacting a compound represented by the formula (VII) or a salt thereof with a compound represented by the following formula (IX) to obtain a compound represented by the following formula (X);
ii-1) preparing a compound represented by the formula (VI) from the compound represented by the formula (X) in the presence of a dehydrating agent;

(IX) (X)
In the compound represented by the above formula, the general formula ^{(IX) R 10, R 11} , R 12, R 13 and the group represented by n in the compound represented by the claim 1 formula ^{(III) R 10, R 11} , R 12, Same as the group represented by R ¹³ and n; R ¹⁰ in the compound represented by the formula ^{(X), R 11, R} 12, R 13 and the group represented by n in the compound represented by the claim 1 formula ^{(III) R 10, R 11} , R 12, R 13 , and same as the group represented by n; Group shown in compounds of the formula (X) with R ^1, R ^3, R ⁴ and W are the same groups represented by R ^1, R ^3, R ⁴ and W in the compound represented by the formula (VII); R ²⁰ represents H or OH; And
iii-1) A compound represented by the formula (VI) wherein R ²⁰ represents OH is represented by R ⁸ COOH, a peptide chain, HOOC-Ar-R ²⁷ , a compound represented by the following formula (IX), or the following formula (XV) Reacting with the compound represented by Formula (XXI) or R ⁸ NCO to obtain a compound represented by Formula (I);

(XXI) (IX) (XV)
In this formula,
In R ⁸ COOH R ⁸ is C _1-6 denotes a hydrocarbyl; R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each independently represent H or C _1-6 hydrocarbyl; Ar represents an aromatic ring or an aromatic heterocyclic ring; R ²⁷ is F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbyl, OC _1-6 hydrocarbyl, OC (O) C _1-6 Consisting of hydrocarbyl, C (O) OC _1-6 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl and S (O) ₂ C _1-6 hydrocarbyl 0-5 identical or different groups selected from the group, wherein the peptide chain has a free carboxyl group and the N-terminus has 0-2 identical or different C _1-6 hydrocarbyl groups or has an amino protecting group, said amino protecting group Is selected from the group consisting of Fmoc, Boc, CBZ, Tr and Alloc;
or
i-2) reacting a compound represented by formula (VII) or a salt thereof with a compound represented by formula (XI) to obtain a compound represented by formula (XIII);
ii-2) preparing a compound represented by the formula (VI) from a compound represented by the following formula (XIII) in the presence of a base;

(XI) (XIII)
In the above formula, 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 (XI) are represented by R in the compound represented by the formula (III) according to claim 1 ^{Is the} same as the group represented by ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² and n; U is selected from the group consisting of Cl, Br, I, OTs (p-toluenesulfonate groups) and OMs (methanesulfonate groups); T is selected from the group consisting of F, Cl, Br, OSu, OBt and OAt; R ¹⁰ in the compound represented by Formula ^{(XIII), R 11, R} 12, R 13, R 21, R 22, a group represented by n and U R ^10, from the compound of the formula (XI) R ^11, R ^{Is the} same as the group represented by ¹² , R ¹³ , R ²¹ , R ²² , n and U; Formula represented by (X) R ^1, in the compound represented by R ^3, R ^4, R ²⁰ and the group represented by W R ^1, from the compound represented by the formula ^{(VII) R 3, R 4} , R 20 and W Same as the group being; And
iii-2) A compound represented by the formula (VI) wherein R ²⁰ represents OH is represented by R ⁸ COOH, a peptide chain, HOOC-Ar-R ²⁷ , a compound represented by the following formula (IX), or the following formula (XV) Reacting with the compound represented by Formula (XXI) or R ⁸ NCO to obtain a compound represented by Formula (I);

(XXI) (IX) (XV)
In this formula,
In R ⁸ COOH R ⁸ is C _1-6 denotes a hydrocarbyl; R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each independently represent H or C _1-6 hydrocarbyl; Ar represents an aromatic ring or an aromatic heterocyclic ring; R ²⁷ is F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbyl, OC _1-6 hydrocarbyl, OC (O) C _1-6 Consisting of hydrocarbyl, C (O) OC _1-6 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl and S (O) ₂ C _1-6 hydrocarbyl 0-5 identical or different groups selected from the group; The peptide chain has a free carboxyl group and has 0 to 2 identical or different C _1-6 hydrocarbyl groups or amino protecting groups at the N-terminus, wherein the amino protecting groups are from the group consisting of Fmoc, Boc, CBZ, Tr and Alloc Selected;
or
i-3) Reaction of a compound represented by the following formula (XIV) with a compound represented by the formula (VIII) or a salt thereof in the presence of basic, acidic or basic and acidic reagents to obtain a compound represented by the formula (VI) step;

(XIV)
In the compounds represented by the general formula ^{(XIV) R 10, R 11} , R 12, R 13, R 21, R 22 and the group represented by n R in the compound represented by the claim 1 formula (III) ^10, R ¹¹ Is the same as the group represented by R ¹² , R ¹³ , R ²¹ , R ²² and n; And
ii-3) A compound represented by the formula (VI) in which R ²⁰ represents OH is represented by R ⁸ COOH, a peptide chain, HOOC-Ar-R ²⁷ , a compound represented by the following formula (IX), or the following formula (XV) Reacting with the compound represented by Formula (XXI) or R ⁸ NCO to obtain a compound represented by Formula (I);

(XXI) (IX) (XV)
In this formula,
In R ⁸ COOH R ⁸ is C _1-6 denotes a hydrocarbyl; R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each independently represent H or C _1-6 hydrocarbyl; Ar represents an aromatic ring or an aromatic heterocyclic ring; R ²⁷ is F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbyl, OC _1-6 hydrocarbyl, OC (O) C _1-6 Consisting of hydrocarbyl, C (O) OC _1-6 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl and S (O) ₂ C _1-6 hydrocarbyl 0-5 identical or different groups selected from the group; The peptide chain has a free carboxyl group and has 0 to 2 identical or different C _1-6 hydrocarbyl groups or amino protecting groups at the N-terminus, wherein the amino protecting groups are from the group consisting of Fmoc, Boc, CBZ, Tr and Alloc Selected;
or
i-4) reacting a compound represented by formula (VII) or a salt thereof with a compound represented by formula (XV) to obtain a compound represented by formula (XVI) or formula (XVII);
ii-4) preparing a compound represented by formula (VI) from a compound represented by formula (XVI) or a compound represented by formula (XVII) in the presence of a dehydrating agent;

(XV) (XVI)

(XVII)
In this formula,
General formula (XV) the formula R ¹⁵ and a group of paragraph 1 of the same group shown in claim 1 formula (IV) a group represented by Q to R ¹⁵ and Q, and represented by R ^15, and Q in formula (XVI) in ( IV) are the same as the groups represented by R ¹⁵ and Q, and the groups represented by R ¹ , R ³ , R ⁴ , R ²⁰ and W in formula (XVI) are represented by R ¹ , R ³ , R ⁴ , tiling the same represented by R ^20, and W, and the same groups represented by R ¹⁵ and Q in the formula (XVII) of claim 1 formula (IV) a group represented by R ¹⁵ and Q in, R ¹ in the general formula (XVII) ^{, R 3, R 4, R} 20 and the same group represented a group represented by W in the compound represented by the formula (VII) with ^{R 1, R 3, R 4} , R 20 and W; And
iii-4) A compound represented by the formula (VI) wherein R ²⁰ represents OH is represented by R ⁸ COOH, a peptide chain, HOOC-Ar-R ²⁷ , a compound represented by the following formula (IX), or the following formula (XV) Reacting with the compound represented by Formula (XXI) or R ⁸ NCO to obtain a compound represented by Formula (I);

(XXI) (IX) (XV)
In this formula,
In R ⁸ COOH R ⁸ is C _1-6 denotes a hydrocarbyl; R ⁸ and R ²⁶ in the compound represented by the formula (XXI) each independently represent H or C _1-6 hydrocarbyl; Ar represents an aromatic ring or an aromatic heterocyclic ring; R ²⁷ is F, Cl, NO ₂ , CN, OH, SH, COOH, NH ₂ , NR ⁸ R ⁹ , C _1-6 hydrocarbyl, OC _1-6 hydrocarbyl, OC (O) C _1-6 Consisting of hydrocarbyl, C (O) OC _1-6 hydrocarbyl, SC _1-6 hydrocarbyl, S (O) C _1-6 hydrocarbyl and S (O) ₂ C _1-6 hydrocarbyl 0-5 identical or different groups selected from the group, wherein the peptide chain has a free carboxyl group and the N-terminus has 0-2 identical or different C _1-6 hydrocarbyl groups or has an amino protecting group, said amino protecting group Is selected from the group consisting of Fmoc, Boc, CBZ, Tr and Alloc. A pharmaceutical composition for the treatment of a tumor or cancer comprising a compound represented by formula (I) according to any one of claims 1 to 8 or a salt thereof. delete 11. The method of claim 10, wherein the tumor or cancer is liver cancer, stomach cancer, breast cancer, lung cancer, bowel cancer, ovarian cancer, pancreatic cancer, head and neck cancer, cervical cancer, kidney cancer, melanoma, prostate cancer, cerebral glioma, various hematologic cancers, lymphomas and multiple A pharmaceutical composition selected from the group consisting of bone marrow cancer. The pharmaceutical composition according to claim 10, wherein the compound represented by formula (I) or a salt thereof is formulated in an injection formulation. The pharmaceutical composition of claim 13, wherein the injection formulation is selected from the group consisting of powder injection, lyophilized powder injection, aqueous solution injection, emulsion and suspension.
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