KR20010074498A - Bioreductive cytotoxic agents - Google Patents

Abstract

The present invention relates to a compound composed of an electroactive alkylation component including an electron withdrawing group, a bioreduction component including at least two double bonds, and a linker connecting the electroactive alkylation component and the bioreduction component.

Description

Bioreducible Cytotoxic Agents {BIOREDUCTIVE CYTOTOXIC AGENTS}

Many cytotoxic agents can be used for chemotherapy, including anti-metabolic agents, antibiotics, alkylating agents, and mitotic inhibitors. These drugs usually destroy both cancer cells and normal cells. There is a need for an anticancer agent that destroys cancer cells preferentially than normal cells.

Because of the pathological nature of cancer cells, cancer cells are distinguished from normal cells in that blood vessels around the cells are poorly organized and do not supply sufficient oxygen to the carcinogenic sites. In other words, the cancer cells are oxygen deficient. These unique physiological properties open the way for the production of cytotoxic agents that can only act on cancer cells.

According to statistics from the American Cancer Society, about four million people have died of cancer since 1990, and cancer is the second largest cause of death in the United States after heart disease. Cancer treatment usually consists of chemotherapy, radiation therapy, hormone therapy, immunotherapy, and surgery. Of these, chemotherapy is the preferred treatment, particularly for inoperable or metastatic cancer.

Summary of the Invention

The present invention relates to a cytotoxic substance consisting of three components: (1) a proactive alkylation component comprising an electron withdrawing group; (2) a bioreducing component comprising at least two double bonds; (3) A linker for linking the totally active alkylation component and the bioreduction component. A "fully active alkylation component" refers to a functional group that, once activated, replaces active hydrogen contained in another substance, such as DNA, with one of its alkyl groups covalently bonded. "Bioreducing component" means an in vivo reduction reaction (electron accepting reaction), i. e., refers to components that can cause bioreduction reactions. Double bonds of the bioreducing component form a conjugated system with them or with the double bond of the bonder. The conjugated system allows electrons to be transferred from the bioreduction component to the electron withdrawing of the fully active alkylation component by the reduction reaction by the bioreduction component. This breaks the bond between the electron withdrawing group and the linker, causing the active alkylating component to turn into an active alkylating compound.

Examples of fully active alkylation components include aromatic groups (e.g., phenyl groups, naphthalene groups) and bis (haloethyl) amino groups substituted with electron withdrawing groups (e.g. esters, urethanes, carbonates). (E.g., bis (chloroethyl) amino group or nitrogen mustard). The bis (haloethyl) amino group becomes an alkylated group in the bioreduction reaction. In the case where the aromatic component in the material is a phenyl group, for each of the two substituents substituted by the phenyl group, substitution at the meta or para position is preferred. And remaining positions in the phenyl group are each independently an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, an amino group, an amino alkyl group, a hydroxy group, a hydroxyalkyl group, Alkoxy group, aryloxy group, aralkoxy group, aralkoxy group, heteroaryloxy group, hetero aralkoxy group, oligoalkylene glycol, amido group, ester group, aralkoxycarbonylamino group, ureido group , Thio, alkylthio group, arylthio group, or heteroarylthio group may be optionally substituted. Among the substituents, alkyl groups, alkoxy groups, oligoalkylene glycols, aryloxy groups, heteroaryloxy groups, and amino groups are preferred. Each of these substituents is preferably substituted at the ortho position relative to the bis (haloethyl) amino group.

The bioreduction component is converted to the second alkylation material by the bioreduction reaction. Some examples of such bioreducing components include 1, 4-benzoquinone (i.e., quinone), nitrobenzene, or 1, 2-dioxocyclohex-3,5-diene. When the bioreducing component is quinone, each of the non-oxo positions (positions where the oxo groups are not bonded) of the quinone ring is independently an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a hetero Aryl group, heteroaralkyl group, amino group, amino alkyl group, hydroxy group, hydroxyalkyl group, alkoxy group, aryloxy group, aryloxy group, alkoxy group, heteroaryloxy group, heteroarkoxy group, Carboxylic group, acyloxyalkyl group, ester group, amido group, amidoalkyl group, sulfoanido group, sulfonylamino group, thio group, alkylthio group, arylthio group, aralkylthio group, heteroarylthio group Or a heteroaralkylthio group may be optionally substituted. The fused ring may optionally contain 1-3 hetero atoms such as nitrogen, oxygen, sulfur.

The linker connecting the fully active alkylation component and the bioreduction component may be selected from one of the following groups: a methylene group, a hydrocarbon consisting of three carbon atoms containing one double bond, and alternating with each other. Hydrocarbons of five carbon atoms with two double bonds. The binder may optionally be substituted with an alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group, or oligoalkylene glycol. If the linker contains two or more substituents, two of the substituents may be linked to form a ring of five or six atoms. The ring formed may be aliphatic or aromatic, and the ring may be substituted with an alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group, or oligoalkylene glycol. In addition, one of three heteroatoms of nitrogen, oxygen, and sulfur may be one of the atoms constituting the ring.

Salts of cytotoxic substances are also within the scope of the present invention. For example, a salt may form between the amino substituents of the cytotoxic substance and the negatively charged ions. Suitable anions include chlorine, hydrogen chloride, bromine, iodine, sulfate, nitrate, phosphate, or acetate. However, the present invention is not limited thereto. Likewise, the negatively charged substituents (eg carboxylates) included in the compounds of the invention are also cationic, e. g., alkali metal ions such as sodium ions, potassium ions; Alkaline earth metal cations such as magnesium cations and calcium cations; Organic salts such as tetramethyl ammonium ions, diisopropyl-ethyl ammonium ions can form salts with one or more substituted ammonium ions.

As used herein, an "alkyl group" refers to a linear or branched hydrocarbon containing 1 to 8 carbon atoms or a cyclic hydrocarbon containing 3 to 8 carbon atoms. The cyclic hydrocarbon may comprise 1 to 3 hetero atoms, such as nitrogen, oxygen, or sulfur, and may comprise a fused ring. The fused ring is a ring that shares a common carbon-carbon bond. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl, hexyl, isohexyl, Heptyl group, octyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, norbornyl group, isobornyl group, cyclohexylmethyl group, 1- or 2-cyclohexylethyl group, 1-, 2 Or 3-cyclohexylpropyl group, tetrahydrofuranyl group, tetrahydropyranyl group (tetrahydropyranyl), piperidine group, morpholino group and pyrrolidine group. However, it is not limited thereto.

"Alkenyl group" means a linear or branched hydrocarbon comprising 2 to 8 carbon atoms or a cyclic hydrocarbon comprising 3 to 8 carbon atoms, having one or more double bonds i. e. means a cycloalkenyl group. The cycloalkenyl group may include 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur, i. e., “heterocycloalkenyl group”, may also contain fused rings. Generally, the alkenyl group includes an allyl group, 2-butenyl group, 2-pentenyl group, 2-hexenyl group, cyclopropenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, cyclooctenyl group, norbornyl Norbornylenyl and the like.

"Aryl group" refers to a cyclic aromatic functional group containing 3 to 8 carbon atoms and may include a fused ring. Fused aryl groups refer to aromatic rings that share a common carbon-carbon bond with other cyclic functional groups. The cyclic functional group may be one of an aryl group, a cycloalkyl group, or a heterocycloalkyl group. Generally, aryl groups include phenyl groups, 1-naphthalene groups, 2-naphthalene groups, biphenyl groups, phenanthryl groups, and anthracyl groups. "Heteroaryl group" means an aryl group containing 1 to 3 heteroatoms. In general, a heterocyclic aromatic ring includes a coumanil group, a pyridyl group, a pyrazinyl group, a pyrimidyl group, a furyl group, a pyrrolyl group, a dienyl group, a thienyl group, a thiazole group, an oxazole group ( oxazolyl), imidazole group, indole group, benzofuran group, benzthiazolyl group, and the like. One example of an aralkyl group is a 2-phenylethyl group.

"Oligoalkylene glycol" means a bond of 2 to 5 alkoxy groups. Each alkoxy group may be the same or different. One example of an oligoalkylene glycol is ethoxymethoxy.

As used herein, substituents such as amino, amido, ester, sulfoamido, sulfonylamino, and ureido may be substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, or heteroaralkyl groups. It may or may not be. In addition, substituents such as amido groups or ester groups may be combined with components adjacent to each functional group. Cyclic groups, e. g., substituents of phenyl groups may be bonded at any possible position.

The present invention also relates to a composition comprising one of the above-described cytotoxic compounds (or salts thereof) and a pharmacologically suitable carrier. The compound is included in an amount appropriate for treating cancer. The present invention also relates to a method for treating cancer, comprising administering such a cytotoxic compound or a salt thereof to a patient in need thereof. Cancers that can be treated by the method include leukemia, lung cancer, colon cancer, central nerve cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer. The use of such cytotoxic substances in the manufacture of a medicament for the treatment of cancer described above is also within the scope of the present invention. Other features and uses of the invention will be apparent from the preferred configuration and claims set forth below.

Detailed description of the invention

The present invention relates to a cytotoxic compound comprising (1) an electroactive alkylating component comprising an electron withdrawing group and (2) a bioreducing component.

Examples of such bioreducing components include the following functional groups:

Examples of such electroactive alkylation components include the following functional groups:

Note that in both examples of the alkylation component the ester group is an electron-withdrawing group.

As described above, the cytotoxic compounds of the present invention can be converted to two alkylating agents by a bioreduction reaction. The mechanism of this transformation can generally be divided into two steps. Hereinafter, the mechanism is specifically described using one example of a cytotoxic compound containing quinone as a bioreducing component, a methylene group as a binder, and a bis (chloroethyl) -amino-phenyl ester as a preactive alkylating agent. As described.

The first step in the mechanism involves the reduction of the bioreducing component. In general, the reduction takes place by the intracellular enzyme, eg, cytochrome P ₄₅₀ reductase kinase (cytochrome P ₄₅₀ reductase). Quinones perform bioreduction reactions in two steps: first to form semiquinone radical anions, and then to form hydroquinone. The semiquinone radical anion is highly reactive with oxygen. In fact, most of the anions are oxidized to quinones in oxygen rich normal tissues.

As described in the prior art, the carcinogenic site is characterized by poorly organized vascular tissue, so that the surroundings of carcinogenic cells generally lack oxygen in comparison with normal cells. That is, at the carcinogenic site, the compound reduced by the above reaction is less likely to react with oxygen and reoxidize. As a result of this, the semiquinone radical anion has a longer half-life and can be reduced once again to produce hydroquinone.

In the second stage of the mechanism, the electron pair moves first from the oxygen of the hydroquinone into the quinone ring (as shown in the figure below, the electron withdrawing group is an ester group and the bond is methylene), and again the electron pair is bioreduced. Through the linker connecting the component and the electroactive alkylation component, it is transferred to the oxygen of the electron withdrawing group included in the electroactive alkylation component. Due to the movement of the electrons, the bond between the bonder and the electron withdrawing group is broken, and the quinone component (bioreduction component) is changed into quinone methide. The quinone meside is a nucleophile, e. g., known as alkylating agents capable of attacking DNA (See Lin et al., J. Med. Chem. 1972, 15, 127; J. Med. Chem. 1973, 16, 1268; J. Med. Chem. 197, 17, 688; J. Med. Chem. 1975, 18, 917; J. Med. Chem. 1976, 19, 1336).

Quinone Meside

By breaking the bond as described above, the electron withdrawal is converted into a functional group that attracts much less electrons. Such conversion, on the contrary, increases the electron density of the bis (haloethyl) amino group, converting the preactive alkylation component into an alkylating agent. Taking the ester group as an example, the bis (chloroethyl) amino alkylation component remains inactive due to the strong electron attraction of the ester group as given by Hammet substitution constants (σ _p = 0.45 and σ _m = 0.37). However, due to the breakage of the bonds described above, when the ester group is changed to a carboxylate (σ _p = 0 and σ _m = −0.1), whose electron attraction is much weaker than that of ester, The electron density of the depleted nitrogen increases, which promotes a reaction in which the fully active alkylation component is converted into an active alkylating agent.

The cytotoxic compound according to the present invention is represented by the following general formula (I).

(I)

Wherein A, B, C, and D are each independently -R^One, -R-NR^OneR², -O-R^One, -R-OH, -C (= O) O-R^One, -R-O-C (= O) R^One, -C (= O) -NR^OneR², -R-NR^One-C (= O) R², -SO₂-NR^OneR², -N = SO₂, -S-R^OneOr -L-W-Ph-N (CH₂CH₂X)₂This can be Optionally, A and B are -L-W-Ph-N (CH₂CH₂X)₂If you do not belong to_,A and B together may form a fused ring with a quinone ring, consisting of 5-6 atoms. Similarly, C and D are -L-W-Ph-N (CH₂CH₂X)₂If you do not belong to_,C and D may together form a Fused ring composed of 5-6 atoms. The fused ring may optionally contain 1 to 3 heteroatoms such as nitrogen and oxygen sulfur, optionally, an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, -R-NR^OneR², -O-R^One, -R-OH, -C (= O) O-R^One, -R-O-C (= O) R^One, -C (= O) -NR^OneR², -R-NR^One-C (= O) R², -SO₂-NR^OneR², -N = SO₂, Or -S-R^OneIt may be substituted by. In the above, R is, independently, an alkyl group or can be erased. Each R^OneAnd R²May independently be hydrogen, an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, or a heteroaralkyl group. L is-(CR³= CR⁴)_n-CR⁵R⁶Denoted by R³, R⁴, R⁵And R⁶Is independently hydrogen, alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group, or-(O-alkyl)_1-5; And n may be 0, 1, or 2. "-(O-alkyl)_1-5"Is an alkoxy group ("-(O-alkyl)_One") Or an oligoalkylene glycol group ("-(O-alkyl)_2-5"). When n is not 0, R³And R⁴May optionally form together a ring consisting of 5 to 6 atoms. The ring may be an aliphatic ring or an aromatic ring, optionally, an alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group, or-(O-alkyl)_1-5It may be substituted by. The ring is 1-3 heteroatoms, e. g., nitrogen, oxygen, or sulfur. W is -O-C (= O)-, -O-C (= O) -NR^One-Or -O-C (= O) O- Ph is a phenyl group, optionally an alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group, -R-NR^OneR², -OH,-(O-alkyl)_1-5, -O-aryl, -O-aralkyl, -O-heteroaryl, -O-heteroaralkyl, -R-OH, -C (= 0) O-R^One, -C (= O) -NR^OneR², -NR^One-C (= O) R², -NR^One-C (= O) O-R², -NR^One-C (= O) NR^OneR²Or -S-R^OneIt may be substituted by. X is halo, e. g., fluoro group, chloro group, bromo group, iodine group.

If A and B do not form a ring fused with a quinone ring and C and D also do not form a ring fused with a quinone ring, then at least one of A, B, C, and D is -LW-Ph-N Remember to be (CH ₂ CH ₂ X) ₂ . And if none of A, B, C, or D is -LW-Ph-N (CH ₂ CH ₂ X) ₂ , then A and B or C and D (including A and B as well as C and D); A ring is fused with a quinone ring. The formed fused ring (wherein at least one fused ring when two fused rings are present) comprises a double bond between two ring atoms, and one of the two ring atoms has -LW- Ph-N (CH ₂ CH ₂ X) ₂ is substituted. The double bond, together with the double bond of the quinone ring, forms a conjugated system that can move electrons from one double bond to another double bond.

Some specific examples of the compound according to Formula I are as follows.

One

2 3

4 5

6 7

9 8

11 10

13 12

15 14

16 17

18 19

20 21

22 23

24 25

The process for producing the compound represented by the formula (I) is divided into three steps: (1) production of a bioreducing quinone component; (2) production of a bis (haloethyl) amino-phenyl component; (3) coupling between the bioreduced quinone component and the bis (haloethyl) amino phenyl component. Specific processes of (1)-(3) are described below:

(1) Generation of quinone ring containing bioreducing component:

It is necessary for the reaction to bind living groups, eg halides, attached to the linker of the appropriately protected bioreducing component, with the desired bis (haloethyl) amino phenyl in step (3) of this process. The living group and the binder may be introduced at the non-NO position of the quinone ring by, for example, an electrophilic substitution reaction. As described in (1) of Example 1, hydroquinone reacts with paraformaldehyde, whereby hydroxymethyl group is formed on carbon ₂ (C ₂ ) of 3, 5, 6-trimethyl-hydroquinone dimethyl ester. do. Since the reaction takes place in a hydrochloric acid solution, the hydroxy methyl group is reacted again so that the hydroxyl group in the group is replaced with chlorine ions. Therefore, such reaction produces quinones which are eventually substituted with chloromethyl groups. Then, the two methyl ester protecting groups are deprotected by hydrolysis.

(2) Production of bis (haloethyl) -phenyl component (In the following description, chloro is used.):

The bis (chloroethyl) amino phenyl component is e. g., nitrobenzoic acid. The carboxylate is protected in the form of an ester group. Suitable substituents applied to the benzene ring may be bound or converted to the benzene ring at this point, e. g., see (2) of Example 1. The nitro group is reduced to form an amino group. The amino group then reacts with ethylene oxide to form an amino group substituted with two hydroxy ethyl groups. Alkylation components, i. e., the bis (chloroethyl) amino component is used in the intermediate containing the bis (hydroxyethyl) amino group in a chlorolation agent, i. e., formed by the addition of thionyl chloride. Like the deprotection reaction of step (1), the ester group becomes carboxylate again by hydrolysis.

(3) Coupling reaction of a bioreducing component containing a quinone ring with a bis (chloroethyl) amino-phenyl component:

In a typical example, a component comprising a quinone ring, e. g., 2-chloromethyl-3, 5, 6-trimethylbenzoquinone of Example 1, the bis (chloroethyl) amino-phenyl component by the nucleophilic substitution reaction, e. g., 3- [bis- (2-chloroethyl) amino-4-methoxy benzoic acid. The carboxylate, which reacts with the nucleophile, is substituted with halogen ions, forming an ester bond.

As described above, pharmaceutical compositions according to the invention comprising an effective amount of a cytotoxic substance may be used to treat cancer. In addition, a method of treating cancer by administering such a composition to a patient is also within the scope of the present invention. An effective amount of a cytotoxic compound (or salt of a cytotoxic compound) is defined as the amount of compound that can be administered to a cancer patient to produce a therapeutic effect on the patient. The effective amount administered to a patient is generally determined based on the patient's age, surface area, weight, and condition. Correlation (body surface area per 1m ² mg) of the dose in animals and humans is Freireich et al., Cancer Chemother. Rde. 1966, 50, 219. Body surface area can be roughly determined by the height and weight of the patient. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardley, New Yorkl, 1970, 537. Effective amounts of cytotoxic substances for practicing the present invention range from about 0.1 mg / kg to 250 mg / kg. Effective dosages may also vary, as is known in the art, depending on the route of administration, whether excipients are used, and the likelihood of the use of other anticancer agents or the combination of other therapeutic methods such as radiation therapy.

The pharmaceutical composition may be administered via parenteral routes, including by mouth, topically, subcutaneously, intraperitoneally, intramuscularly, and intravenously. Examples of parenteral modes of administration include taking an aqueous solution of the active agent with isotonic saline, 5% glucose, or other well-known pharmaceutically applicable excipients. Soluble preparations such as cyclodextrins or other solubilizing agents known to those skilled in the art can be used as pharmaceutical excipients for the administration of therapeutic compounds.

Cytotoxic compounds according to the invention may also be formulated in dosage forms for other routes of administration using methods well known in the art. The pharmaceutical compositions may be formulated in dosage forms for oral administration such as, for example, capsules, gel seals, or tablets. The capsule may be composed of a conventionally well-known pharmaceutically acceptable substance such as gelatin or cellulose derivatives. The tablets may be prepared according to conventional methods by compressing the active compound of the present invention, a solid carrier, and a lubricant. Examples of such solid carriers include starch and sugar bentonite. The cytotoxic compounds may be taken in the form of tablets or capsules of hard shell, including, for example, lactose or mannitol as binders, customary excipients, and tableting agents. The anticancer effect of the compounds according to the invention can be assessed in advance by a tumor groth regression assay that assesses the ability of the test compound to interfere with the growth of cancer cells in the body of rats. The assay can be done by implanting cancer cells into fat pads of hairless mice. The cancer cells are then allowed to grow to a certain size before the cytotoxic compound is administered. The size of cancer cells is several weeks, e. g., observed for 3 weeks. The general health of the subject organism during the analysis is also observed.

If there is no further assimilation, it would be apparent to one skilled in the art that the present invention may be carried out fully on the basis of the above detailed description. The following examples are directed to the preparation and biological analysis of various compounds according to the invention, which are appended only to detail the invention and do not in any way limit the scope of the invention.

Each of Examples 1-7 details the preparation of seven cytotoxic compounds according to the invention. Each example is divided into three parts: (1) production of a bioreducing quinone component, (2) production of a bis (chloroethyl) amino-phenyl component, and (3) binding of the two components.

Example 1

Synthesis of Compound 1

(1) Synthesis of 2-chloromethyl-3, 5, 6-trimethylbenzoquinone

Hydrogen chloride gas is injected into a mixture of 3, 5, 6-trimethylhydroquinone dimethylether (1 g, 5.5 mmol) and paraformaldehyde (1 g) in an acetic acid solution containing 1N hydrochloric acid (30 ml). The reaction mixture is then mixed at 60 ° C. for 1 hour. The mixture is poured into 400 ml of water and filtered. The filtered residue is dissolved in 100 ml of ethyl acetate and the solution is washed with saturated NaCl (100 ml) solution. The extract in the process is dried over magnesium sulfate and the solvent is removed under reduced pressure. Methyl 4-2-chloromethyl-3, 5, 6-trimethylhydroquinone dimethyl ether is produced in the form of a white solid (0.8 g, 6%). ¹ H NMR (300 MHz, CDCl ₃ ): 4.47 (s, 2H), 3.79 (s, 3H), 3.66 (s, 3H), 2.3 (s, 2H), 2.20 (s, 3H), 2.18 (s, 2H). ESMS Calc. for Cl ₂ H ₁₉ ClO ₂ : 230.73; Found: 231.7 (M + H).

0.8 g (3.5 mmol) of 2-chloromethyl-3, 5, 6-trimethyl-hydroquinone dimethyl ether is dissolved in 20 ml of acetonitrile. After adding a solution of 9.6 g of Ammonium Serin (IV) nitrate in 200 ml of water, the mixture is extracted with ethyl acetate (twice 100ml and 50ml, respectively). The mixed extract is dried over magnesium sulfate and the solvent is removed under reduced pressure. 50 ml of water is added to the residue, and the mixture is extracted with ethyl acetate (50 ml). The extract is washed with saturated NaCl solution (100 ml). The extract is dried over magnesium sulfate, and the solvent is removed under reduced pressure to form 2-chloromethyl-3, 5, 6-trimethylbenzoquinone in the form of yellow crystals. ¹ H NMR (300 MHz, CDCl ₃ ): 4.47 (s, 2H), 2.16 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). ESMS Calc. for C ₁₀ H ₁₁ ClO ₂ : 198.65; Found: 199.6 (M + H).

(2) Synthesis of 3-bis (2'-chloroethyl) amino-4-methoxybenzoic acid

The reaction mixture of methyl 3-amino-4-methoxybenzoate (10.94 g, 0.06 mol) and ethylene oxide (12.5 g, 0.28 mol) in acetic acid solvent (150 ml) is mixed for 24 hours at room temperature. It is then condensed to 80 ml in a rotary evaporator, diluted again with water (300 ml) and extracted with dichloromethane / ethyl acetate (1: 1, 6 × 300 ml). The organic solution is condensed to produce a whitened oil (8.6 g, 54%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.85 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.52 (m, 4H) , 3.24 (m, 4 H).

To a benzene solution (40 ml) of methyl 3- (2'-bis (hydroxyethyl) amino) -4-methoxybenzoate (2.80 g, 10.40 mmol) add cionyl chloride (1.2 ml) and mix at room temperature . After such addition, the reaction slurry is heated to reflux for 0.5 hours. The reaction mixture is then treated with ice / water (100 ml) and extracted with ethyl acetate (100 ml). The ethyl acetate solution was washed with sodium bicarbonate (100 ml), dried over magnesium sulfate and then condensed to yield the result as a white solid (2.5 g, 79%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.76 (dd, J = 8.4, 2.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.52 (s, 8H). ESMS Calcd. for C ₁₃ H ₁₇ Cl ₂ NO ₃ : 305.1; Found: 328.0 (M + Na).

A suspension of methyl 3-bis (2'-chloroethyl) amino-4-methoxybenzoate (2.70 g, 8.823 mmol) in concentrated hydrochloric acid solution (37% w / w in H ₂ O) was stirred for 1 hour under nitrogen gas. Heated to reflux. The reaction mixture is treated with ice / water (200 ml) and extracted with ethyl acetate (4 × 150 ml). The organic solution is condensed to yield a white solid (2.05 g, 80%). ESMS calcd for C ₁₂ H ₁₅ Cl ₂ NO ₃ : 291.0; Found: 292.0 (M + H).

(3) binding between intermediates synthesized in (1) and (2)

Acetone solution of 3-bis (2'-chloroethyl) amino-4-methoxy benzoic acid (0.51 g, 1.750 mmol) with 2-chloromethyl-3, 5, 6-trimethylbenzoquinone (0.56 g, 2.819 mmol) 25 ml) is heated under reflux for 2 hours in a nitrogen gas state in the presence of potassium carbonate (2.0 g) and sodium iodide (1.2 g). In the process, the organic layer is separated, diluted with ethyl acetate (50 ml), washed with aqueous potassium carbonate solution (2 x 50 ml), dried over magnesium sulfate, and condensed to maintain. Flash chromatography on silica gel produced the product in an adhesive oily form (0.61 g, 77%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.70 (dd, J = 8.4, 1.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.25 (s, 3H), 3.90 (s, 3H), 3.50 (s, 8H), 2.18 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). ESMS Calcd. for C ₂₂ H ₂₅ Cl ₂ NO ₅ : 453.1; Found: 454.1 (M + H).

Example 2

Synthesis of Compound 2

(1) It is the same as the method of (1) of Example 1.

(2) Same as Example 2, except that the starting material is 3-amino-4-methylbenzoate instead of 3-amino-4-methoxybenzoate.

(3) binding between intermediates synthesized in (1) and (2)

3-methyl-4-bis (2'-chloroethyl) aminobenzoic acid (830 mg, 3.02 mmol) and 2-chloroethyl-3, 5, 6-trimethylbenzo-quinone (400 mg, 2.51 mmol) were acetone (20 ml) and heated to 500 ° C. for 1.5 h in the presence of potassium carbonate (1 g) and sodium iodide (80 mg). The mixture is poured into 300 ml of water and extracted with ethyl acetate (100 ml, 4 times). The extract is dried over magnesium sulfate and then condensed under dark rock. Quinone-Mustard A is produced in the form of oil or fat (800 mg, 72%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.75 (dd, J = 2.19, 2.19 Hz, 1H), 7.63 (m, 1H), 6.65 (d, J = 8.52, 1H), 5.22 (s, 2H), 3.48 (m, 8H), 2.31 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H). ESMS Calcd. for C ₂₂ H ₂₅ Cl ₂ NO ₄ : 438.31; Found: 439.0 (M + H).

Example 3

Synthesis of Compound 3

(1) Same as (1) in Example 1.

(2) Synthesis of 4-bis (2'-chloroethyl) amino-3-octoxybenzoic acid.

A slurry of 3-hydroxy-4-nitrobenzene (5.5 g, 0.028 mol), iodooctane (10.0 g, 0.042 mol), and potassium carbonate (20 g) in DMF (100 ml) solvent is mixed at 100 ° C. for 3 hours. . The reaction mixture is cooled to room temperature, diluted with water (500 ml) and then extracted with ether / ethyl acetate (9/1, 2 × 200 ml). The mixed organic solution is washed with water (400 ml), dried over sodium sulphate and condensed to form a white oily fat (8.7 g, 100%).

A methanol solution (150 ml) of methyl 4-nitro-3-octoxybenzoate (8.7 g, 0.028 mol) is mixed under hydrogen gas for 10 hours at room temperature in the presence of 10% Pd-C. The reaction mixture is filtered through Celite and condensed to form a white solid (7.6 g, 96%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.25 (d, J = 2.1 Hz, 1H), MS Calcd for C ₁₆ H ₂₅ NO ₃ : 279.2: Found: 279.

An acetic acid solution of methyl 4-amino-3-octoxybenzoate (3.47 g, 12.4 mmol) and ethylene oxide (4.5 g, 198 mol) is mixed at room temperature for 12 hours. The resulting solution is diluted with water (500 ml) and extracted with chloroform / methanol (95/5, 4 × 100 ml). The organic solution is condensed to form a brown fat or oil. Flash chromatography purification (silica gel, 5% to 10% methanol in chloroform) results in the formation of a white oily fat (2.25 g, 42%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.62 (dd, J = 8.1, 2.1 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.06 (t, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.64 (t, J = 5.1 Hz, 4H), 1.86 (J = 5.1 Hz, 2H), 1.30 (m, 10H). 0.89 (t, J = 6.9 Hz, 3H), ESMS Calcd. for C ₂₀ H ₁₃ NO ₅ : 367.2; Found: 390.3 (M + Na).

Cyanyl chloride ((1.2 ml, 16 mmol) is slowly added to a benzene solution (50 ml) of methyl 4-bis (2'-hydroxyethyl) amino-3-octoxybenzoate (2.20 g, 6.0 mol) and room temperature Slowly mix in. After the addition is complete, the reaction mixture is refluxed for 1.5 hours, then the reaction mixture is cooled to room temperature, treated with ice / water (100 ml) and extracted with ethyl acetate (50 ml). The organic solution was washed with sodium bicarbonate (20 ml) and water (50 ml), dried over magnesium sulfate, and condensed to give the result as a white oily fat (2.1 g, 87%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.58 (dd, J = 8.1, 1.8 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 4.03 (t, J = 6.6 Hz, 1H), 3.89 (s, 3H), 3.60 (m, 8H), 1.85 (J = 7.2 Hz, 2H), 1.30 (m, 10H) .0.89 (t, J = 6.9 Hz , 3H), ESMS _Calcd . For C ₂₀ H _{3 ′ 1} Cl ₂ NO ₃ : 403.2; Found: 404.2 (M + H).

A suspension of 4-bis (2′-chloroethyl) amino-3-octoxybenzoate (1.8 g, 4.5 mmol) in saturated hydrochloric acid solution (37% w / w in H ₂ O, 50 ml) was purged with nitrogen gas for 0.5 h. Under reflux under heating. The reaction mixture is treated with ice / water (100 ml) and extracted with chloroform (3 × 50 ml). The organic solution is condensed to a brown fat. Flash chromatography purification (silica gel, 2% methanol in chloroform) gave the result as a white solid (1.58 g, 88%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.67 (dd, J = 8.1, 1.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.40 (d, J = 6.6 Hz, 2H), 3.65 (m, 8H), 1.85 (J = 7.8 Hz, 2H), 1.35 (m, 10H), 0.90 (t, J = 6.6 Hz, 3H), ESMS Calcd. for C ₂₉ H ₂₉ Cl ₂ NO 3: 389.2; Found: 390.2 (M + H).

(3) binding between intermediates synthesized in (1) and (2)

The procedure as described in (1) of the first and second embodiments is performed. ¹ H NMR: σ 7.76 (dd, J = 8. And 1.8 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 8. Hz, 1H), 5.25 (s, 2H ), 3.53 (brs, 8H), 3.6 (t, J = 5.0 Hz, 2H), 2.18 (s, 3H), 2.0 (s, 3H). 2.02 (s, 3H), 1.86 (J = 5.0 Hz, 8H), 1.30 (m, 10H), 0.89 (t, J = 6.9 Hz, 3H), ESMS Calcd. for C ₂₉ H ₃₉ Cl ₂ NO ₅ : 552.2; Found: 553.1 (M + H).

Example 4

Synthesis of Compound 4

(1) same as (1) of Example 1

(2) Synthesis of 2-bis (2'-chloroethyl) amino-3,5-dimethylbenzoic acid

The reaction mixture of methyl 2-amino-3, 5-dimethylbenzoate (7.0 g, 0.039 mol) and ethylene oxide (10 g, 0.23 mol) in acetic acid solvent (150 ml) is mixed for 19 hours at room temperature. It is then condensed to 100 ml in a rotary evaporator, diluted again with water (300 ml) and extracted with chloroform (5 x 200 ml). The organic solution is condensed to produce a whitened oil (10.0 g, 96%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.31 (br s, 1 H), 7.16 (br s, 1 H), 3.91 (s, 3 H), 3.73 (m, 2 H), 3.63 (m, 2H), 3.26 ( br m, 4H), 2.32 (s, 3H), 2.30 (s, 3H).

Cyanyl chloride (12 ml, 0.16 mol) is slowly added to a benzene solution (200 ml) of methyl 2-bis (2'-hydroxyethyl) amino-3, 5-dimethylbenzoate (7.0 g, 0.026 mol), Mix at room temperature. After such addition, the reaction slurry is mixed at room temperature for 12 hours. The reaction mixture is then treated with ice / water (500 ml) and extracted with ethyl acetate (2 × 300 ml). The ethyl acetate solution was washed with water (300 ml) and sodium bicarbonate (200 ml) respectively, dried over magnesium sulfate and then condensed to yield the result in a clear oily form (5.6 g, 71%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.31 (d, J = 2.1 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 3.88 (s, 3H), 3.53 (m, 4H), 3.37 (br m, 4H). 2.35 (s, 3H), 2.30 (s, 3H), ESMS Calcd. for C ₁₄ H ₁₉ Cl ₂ NO 2: 303.1; Found: 304.1 (M + H).

A suspension of methyl 2-bis (2'-chloroethyl) amino-3, 5-dimethylbenzoate (5.6 g, 0.018 mol) in concentrated hydrochloric acid solution (37% w / w in H ₂ O, 150 ml) was added under nitrogen gas. Heated under reflux for 6 hours. The reaction mixture is treated with ice / water (200 ml) and extracted with chloroform (3 × 150 ml). The organic solution is condensed to yield a white solid (5.1 g, 96%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.01 (d, J = 1.5 Hz, 1 H), 7.23 (dd, J = 1.5, 0.6 Hz, 1 H), 3.6 (m, 8 H), 2.43 (s, 3 H ), 2.35 (s, 3 H). ESMS Calcd. for C ₁₃ H ₁₇ Cl ₂ NO ₂ : 289.1.

(3) binding between intermediates synthesized in (1) and (2)

Acetone solution (15 ml) of 2-bis (2'-chloroethyl) amino-3, 5-dimethyl benzoic acid (0.45 g, 1.551 mmol) was prepared in the presence of potassium carbonate (1.5 g) and sodium iodide (1.0 g). Heated under reflux in a nitrogen gas state. To the resulting solution is slowly added acetone solution (5 ml) of 2-chloromethyl-3, 5, 6-trimethylbenzoquinone (0.45 g, 2.413 mmol). After refluxing for 20 minutes, the reaction mixture is cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The organic layer is washed with water (50 ml), dried over magnesium sulfate and then condensed to maintain. Flash chromatography on silica gel produced the product in an adhesive oily form (0.52 g, 76%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.25 (d, J = 2.1 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 5.24 (s. 2H), 3.49 (m, 4H), 3.38 (br m, 4H), 2.33 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 2.07 (s, 3H), 2.06 (s, H). ESMS Calcd. for C ₂₃ H ₂₇ Cl ₂ NO ₄ : 451.1; Found: 452.2 (M + H).

Example 5

Synthesis of Compound 5

(1) 2- (2-acetoxyethyl) -benzoquinone was used as starting material, and the rest was as in (1) part of Example 1.

(2) 4-nitro benzoic acid was used as starting material and the remainder is the same as (2) part of Example 1.

(3) Dioxane of 2-chloroethyl-5- (2'-acetoxyethyl) benzoquinone (110 mg, 0.453 mmol) and 4-bis (2'-chloroethyl) aminobenzoic acid (80 mg, 0.305 mmol) The solution (6 ml) is mixed for 5 meals at room temperature in the presence of potassium carbonate. The reaction mixture is diluted with hexane (15 ml) and filtered through celite. The organic layer is condensed and retained. Flash chromatography on silica gel gave the product as a yellow solid (18 mg, 12%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.97 (d, J = 9.0 Hz, 2H), 6.80 (m, 4H), 5.20 (d, J = 1.8 Hz, 2H), 4.26 (t, J = 6.3 Hz , 2H), 3.83 (t, J = 6.6 Hz, 4H), 3.68 (t, J = 6.6 Hz, 2H), 2.76 (dt, J = 6.0, 1.2 Hz, 2H), 2.03 (s, 3H). ESMS Calcd. for C ₂₂ H ₂₃ Cl ₂ NO ₆ : 467.1; Found: 490.0 (M + Na).

Example 6

Synthesis of Compound 6

(1) A procedure similar to (1) of Example 1 is followed for the synthesis of 2, 3-dimethylbenzoquinone.

(2) Same as (2) in Example 1.

(3) 3-bis (2'-chloroethyl) amino-4-methoxybenzoic acid (180 mg, 0.618 mmol) is dissolved in acetone (10 ml) and heated under reflux in the presence of potassium carbonate (0.58 g). Acetone solution (5 ml) of 2, 3-bischloromethyl-5, 6-dimethylbenzoquinone (75 mg, 0.323 mmol) was added dropwise to the resultant. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (15 ml), washed with aqueous potassium carbonate solution (2 x 50 ml), dried over magnesium sulfate and then condensed to maintain. Flash chromatography purification on silica gel produces the result as a sticky fat (85 mg, 37%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.59 (m, 4H), 6.75 (d, J = 9.0 Hz, 2H), 5.39 (s, 4H), 3.86 (s, 6H), 3.48 (m, 16H) , 2.08 (s, 6 H). ESMS calcd for C ₃₄ H ₃₈ Cl ₂ N ₂ O ₈ : 742.1; Found: 789.1 (M + 2Na + H).

Example 7

Synthesis of Compound 7

(1) Same as (1) in Example 1.

(2) Synthesis of methyl 4-bis (2'-chloroethyl) amino-3- (2 '-(2' '-methoxyethoxy) ethoxy) benzoic acid.

3-hydroxy-4-nitrobenzoate (5.5 g, 0.028 mol), 1-bromo-2- (2-methoxyethoxy) ethane (10.0 g, 0.055 mol), and potashium in DMF (100 ml) solvent The slurry of carbonate (20 g) is mixed at 90-100 ° C. for 2 hours. The reaction mixture is cooled to room temperature and diluted with water (400 ml). The resulting solid is collected by filtration, washed with water (100 ml) and then dried to form a white solid (6.2 g, 74%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.82 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.69 (dd, J = 8.1, 1.2 Hz, 1H), 4.33 (t, J = 4.5 Hz, 2H), 3.95 (s, 3H), 3.92 (t, d, J = 4.8 Hz, 2H), 3.73 (m, 2H), 3.55 (m, 2H), 3.38 (s, 3H). ESMS Calcd. for C ₁₃ H ₁₇ NO ₇ : 299.1; Found: 300.1 (M + H).

A methanol solution (200 ml) of methyl 3- (2 '-(2''-methoxyethoxy) ethoxy) -4-nitrobenzoate (6.0 g, 0.020 mol) was added under hydrogen gas to 10% Pd-C. And mix for 20 hours at room temperature in the presence of acetic acid. The reaction mixture is filtered through Celite and condensed to form a white solid (5.0 g, 93%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.55 (d, J = 8.7, 2.4 Hz, 1H), 7.47 ((d, J = 1.8 Hz, 1H), 6.67 ((d, J = 8.7 Hz, 1H), 4.22 (t, J = 4.8 Hz, 2H), 3.87 (m, 2H), 3.85 (s, 3H), 3.70 (t, J = 4.8 Hz, 2H), 3.58 (t, J = 4.8 Hz, 2H), 3.39 (s, 3 H) .MS Calcd for C ₁₃ H ₁₉ NO ₅ : 269.1: Found: 270.1 (M + H).

Acetic acid solution of methyl 4-amino-3- (2 '-(2''-methoxyethoxy) ethoxy) benzoate (5.0 g, 18.6 mmol) with ethylene oxide (8.8 g, 200 mol) (150 mL) The phosphorus reaction mixture is mixed at room temperature for 12 hours. The resultant is diluted with water (300 ml) and extracted with chloroform / methanol (95/5, 4 × 200 ml). The organic solution is condensed to form a white oily fat (6.1 g, 92%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.62 (dd, J = 8.1, 2.1 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 4.22 (m, 4H), 3.89 (s, 3H), 3.9-3.8 (m, 4H), 3.68 (m, 6H), 3.58 (m, 2H). 3.38 (m, 2 H), 3.37 (s, 2 H). ESMS Calcd. for C ₁₇ H ₂₇ NO ₇ : 357.2; Found: 358.3 (M + H).

To a benzene solution (100 ml) of methyl 4-bis (2'-hydroxytyl) amino-3- (2 '-(2''-methoxyethoxy) ethoxy) benzoate (5.0 g, 13.3 mol) Cyanyl chloride (5.1 ml, 68 mmol) is added slowly and mixed at room temperature. After the addition is complete, the reaction mixture is mixed for 16 hours at room temperature. The reaction mixture is then treated with ice / water (100 ml) and then extracted with ethyl acetate (2 × 300 ml). The mixed ethyl acetate solution was washed with sodium bicarbonate (20 ml) and water (50 ml), dried over sodium sulfate, and condensed to give the result as a white oily fat (3.9 g, 74%). . ¹ H NMR (300 MHz, CDCl ₃ ): 7.58 (dd, J = 8.7, 2.1 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.18 (m, 2H), 3.87 (m, 2H), 3.86 (s, 3H), 3.69 (m, 2H), 3.63 (m, 8H). 3.56 (m, 2 H), 3.37 (s, 3 H). ESMS Calcd. for C ₁₇ H ₂₅ Cl ₂ NO ₅ : 393.1; Found: 394.2 (M + H).

4-bis (2'-chloroethyl) amino-3- (2 '-(2''-methoxyethoxy) ethoxy) benzoate in saturated hydrochloric acid solution (37% w / w in H ₂ O, 50 ml) (3.0 g, 7.64 mmol) is heated with reflux under nitrogen gas for 2 hours. The reaction mixture is treated with ice / water (100 ml) and extracted with chloroform (2 × 100 ml). The organic solution is condensed to a white solid (2.8 g, 97%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.68 (dd, J = 8.4, 2.1 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.22 (m, 1H), 3.89 (m, 2H), 3.67 (m, 10H), 3.62 (m, 2H), 3.39 (s, 3H), ESMS Calcd. for C ₁₆ H ₂₃ Cl ₂ NO ₅ : 379.1; Found: 408.2 (M + H).

(3) binding between the intermediates synthesized in (1) and (2).

It is based on the same process as Example (3). ¹ H NMR: σ 7.58 (dd, J = 8.7, 2.1 Hz, 1H), 7.9 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 5.26 (s, 2H), .18 (m, 2H), 3.87 (m, 2H), 3.69 (m, 2H), 3.63 (m, 8H). 3.56 (m, 2H), 3.37 (s, 3H), 2.12 (s, 3H), 2.05 (s, 3H), 2.02 ((s, 3H) .ESMS Calcd. For C ₂₆ H ₃₃ Cl ₂ NO ₇ : 52.2 Found: 53.1 (M + H).

The following compounds can be synthesized by similar procedures to those described above.

Example 8

Synthesis of Compound 8

¹ H NMR: σ 7.59 (dd, J = 8., 2.1 Hz, 1H), 7.1 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 8.Hz, 1H), 5.23 (s, 3H ), 3.87 (d, J = 6.6 Hz, 2H), 2.63 (q, J = 7.2 Hz, H), 3.65 (s, 8H), 1.30 (m, `1H). 1.10 (t, J = 7.2 Hz, 6H), 0.68 (m, 2H), 0.38 (m, 2H). ESMS Calcd. for C ₂₈ H ₃₆ Cl ₂ N ₂ O ₅ : 551.2; Found: 552.1 (M + H).

Example 9

Synthesis of Compound 9

¹ H NMR: σ 7.58 (dd, J = 8.7, 2.1 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 5.06 (q, J = 7 Hz, 1H), 3.92 (t, 7 Hz, 1H), 3.63 (m, 8H), 3.56 (m, 2H), 2.12 (s, 2H). 2.05 (s, 2H), 2.02 (s, 3H), 1.80 (m, 2H), 1.45 (s, 2H), 1.00 (d, J = 7 Hz, 3H). ESMS Calcd. for C ₂₆ H ₃₃ Cl ₂ NO ₅ : 510.1; Found: 511.2 (M + H).

Example 10

Synthesis of Compound 10

¹ H NMR: σ 7.62 (dd, J = 8., 2.1 Hz, 1H), 7.5 (d, J = 2.1 Hz, 1H), 37.30 (d, J = Hz, 1H), 6.85 (d, J = 8 , 1H), 6.0 (d, J = Hz, 1H), 625 (d, J = Hz, 1H), 5.23 (s, 2H), .50 (s, 2H). 3.85 (s, 6H), 3.65 (s, 8H), 2.05 (s, 3H), 2.00 (s, 3H). ESMS Calcd. for C ₂₇ H ₃₀ Cl ₂ N ₂ O ₆ : 59.2; Found: 550.1 (M + H).

Example 11

Synthesis of Compound 11

¹ H NMR: σ 7.58 (dd, J = 8.7, 2.1 Hz, 1H), 7.9 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 5.26 (s, 2H), .18 (m, 2H), 3.92 (s, 3H), 3.87 (m, 2H), 3.69 (m, 2H), 3.63 (m, 8H). 3.56 (m, 2H), 3.37 (s, 3H), 2.05 (s, 3H), 2.02 ((s, 3H) .ESMS Calc.for C ₂₆ H ₃₃ Cl ₂ NO ₈ : 558.2; Found: 559.1 (M + H).

Example 12

Synthesis of Compound 12

¹ H NMR: σ 7.52 (dd, J = 8.4, 2.1 Hz, 1H), 7.7 (d, J = 2.1 Hz, 1H), 7.7 (d, J = 2.1 Hz, 1H), 7.7 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 5.25 (s, 2H), 3.98 (d, J = 6.9 Hz, 2H), 3.60 (m, 8H), 2.82 (m, 1H). 2.25-2.1 (m, 2H), 2.18 (s, 3H), 2.05 (s, 3H), 2.0 (s, 3H), 2.0-1.7 (m, H). ESMS Calcd. for C ₂₆ H ₃₃ Cl ₂ NO ₈ : 558.2; Found: 559.1 (M + H).

Example 13

Synthesis of Compound 13

¹ H NMR: σ 7.59 (dd, J = 8.4, 2.1 Hz, 1H), 7.1 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.23 (s, 3H), 3.87 (d, J = 6.6 Hz, 2H), 2.63 (q, J = 7.2 Hz, H), 3.65 (s, 8H), 2.15 (s, 3H), 2.08 (s, 3H). 2.0 (s, 3H), 1.30 (m, 1H), 1.10 (t, J = 7.2 Hz, 6H), 0.68 (m, 2H), 0.38 (m, 2H). ESMS Calcd. for C ₂₈ H ₃₆ Cl ₂ N ₂ O ₅ : 551.2; Found: 552.1 (M + H).

Example 14

Synthesis of Compound 14

¹ H NMR: σ 7.4 (dd, J = 8.7, 1.8 Hz, 1H), 7.0 (d, J = 1.8 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 5.38 (s, 2H), 3.96 (t, J = 6.6 Hz, 2H), 3.56 (m, 8H), 2.08 (s, 3H), 2.0 (s, 3H), 1.80 (m, 2H). 1.80 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3H). ESMS Calcd. for C ₂₅ H ₂₉ Cl ₂ N ₂ O ₅ : 522.2; Found: 523.1 (M + H).

Example 15

Synthesis of Compound 15

¹ H NMR: σ 7.4 (dd, J = 8.7, 1.8 Hz, 1H), 7.0 (d, J = 1.8 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 5.38 (s, 2H), .67 (m, 2H), 3.96 (t, J = 6.6 Hz, 2H), 3.91 (s, 3H), 3.56 (m, 8H), 2.23 (s, 3H). 2.08 (s, 3H), 1.80 (m, 2H), 1.8 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). ESMS Calcd. for C ₂₈ H ₃ Cl ₂ N ₂ O ₆ : 565.2; Found: 566.1 (M + H).

Example 16

Synthesis of Compound 16

¹ H NMR: σ 7.4 (dd, J = 2.19, 2.19 Hz, 1H), 7.63 (m, 1H), 6.65 (d, J = 8.52 Hz, 1H), 5.22 (s, 2H), 3.8 (m, 8H ), 2.31 (s, 3H), 2.15 (s, 3H), 2. (s, 3H), 2.0 (s, 3H). ESMS Calcd. for C ₂₂ H ₂₅ Cl ₂ NO: 38.31; Found: 29.0 (M + H).

Example 17

Synthesis of Compound 17

¹ H NMR: σ 7.76 (dd, J = 8. And, 1.8 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 8. Hz, 1H), 5.30 (s, 2H), 3.53 (brs, 8H), 2.35 (s, 3H), 2.18 (s, 3H), 2.0 (s, 3H), 2.02 (s, 3H). ESMS Calcd. for C ₂₂ H ₂₅ Cl ₂ NO: 22.1; Found: 823.1 (M + H).

Example 18

Synthesis of Compound 18

¹ H NMR: σ 7.70 (dd, J = 8., 1.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 6.86 (d, J = 8 Hz, 1H), 5.25 (s, 3H) , 3.90 (s, 3H), 3.50 (s, 8H), 2.18 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). ESMS Calcd. for C ₂₂ H ₂₅ Cl ₂ NO ₅ : 53.1; Found: 5.1 (M + H).

Example 19

Synthesis of Compound 19

¹ H NMR: σ 7.76 (dd, J = 8. And, 1.8 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 8. Hz, 1H), 5.22 (s, 2H), 3.68-3.80 (brm, H), 3.53 (brs, 8H), 3.6 (t, J = 5.0 Hz, 2H), 2.58-2.6 (bm, H), 2.0 (s, 3H). 2.02 (s, 3 H), 1.86 (J = 5.0 Hz, 2 H). 1.30 (m, 10 H), 0.89 (t, J = 6.9 Hz, 3H). ESMS Calcd. for C ₃₁ HCl ₂ N ₂ O ₆ : 611.2; Found: 612.1 (M + H).

Example 20

Synthesis of Compound 20

¹ H NMR: σ 7.4 (dd, J = 2.19, 2.19 Hz, 1H), 7.63 (m, 1H), 6.65 (d, J = 8.52 Hz, 1H), 5.22 (s, 2H), 3.90 (s, 3H ), 3.8 (m, 8H), 2.0 (t, J = 7 Hz), 2.15 (s, 3H), 2.0 (s, 3H). 2.0 (s, 3H), 1.65 (m, 2H), 1.3 (m, 2H), 0.92 (t, J = 8 Hz). ESS Calcd. for C ₂₆ H ₃₂ Cl ₂ N ₂ O ₆ : 539.2; Found: 50.1 (M + H).

Example 21

Synthesis of Compound 21

¹ H NMR: σ 7.4 (dd, J = 2.19, 2.19 Hz, 1H), 7.63 (m, 1H), 7.20 (m, 5H), 6.65 (d, J = 8.52, 1H), 5.22 (s, 2H) , 5.18 (s, 2H), 3.80 (s, 6H), 3.8 (m, 8H), 2.15 (s, 3H). 2. (s, 3 H), 2.0 (s, 3 H). ESMS Calc. for C ₃₀ H ₃₃ Cl ₂ N ₂ O ₆ : 602.2; Found: 603.1 (M + H).

Example 22

Synthesis of Compound 22

¹ H NMR: σ 8.20 (d, J = 7.0 Hz, 1H), 8.11 (d, J = 7.0 Hz, 1H), 7.70 (dd, J = 8., 1.8 Hz), 7.65 (d, J = 1.8, 1H), 7.53 (m, 2H), 6.86 (d, J = 8. Hz, 1H), 5.25 (s, 3H), 3.90 (s, 3H), 3.50 (s, 8H). 2.18 (s, 3 H). ESMS Calcd. for C ₂ H ₂₃ Cl ₂ NO ₅ : 76.1; Found: 77.0 (M + H).

Example 23

Synthesis of Compound 23

¹ H NMR: σ 7.76 (dd, J = 8.4, 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J = 8.Hz, 1H) , 5.23 (s, 2H), 3.90 (s, 3H), 3.50 (s, 8H), 2.26 (s, 3H), 2.03 (s, 3H). ESMS Calcd. for C ₂₃ H ₂₃ Cl ₂ NO ₆ : 80.1; Found: 81.2 (M + H).

Example 24

Synthesis of Compound 24

¹ H NMR: σ 7.4 (dd, J = 8.7, 1.8 Hz, 2H), 7.0 (d, J = 1.8 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 5.38 (s, H), 3.96 (t, J = 6.6 Hz, H), 3.56 (m, 16H), 1.80 (sexet, J = 7.5 Hz, H), 1.8 (sexet, J = 7.5 Hz, H), 0.99 (t, J = 7.2 Hz, 6H). ESMS Calcd. for C ₀ H ₅₀ ClN ₂ O ₈ : 826.2; Found: 827.1 (M + H).

Example 25

Synthesis of Compound 25

¹ H NMR: σ 7.80 (dd, J = 2.19, and 2.19 Hz, 1H), 7.53 (m, 1H), 6.6 (d, J = 8.52, 1H), 5.22 (s, 2H), 3.80 (s, 3H ), 3.8 (m, 8H), 2.3 (s, 3H), 2.31 (s, 3H), 2.15 (s, 3H). 2. (s, 3 H). ESMS Calc. for C ₂ H ₂₈ Cl ₂ N ₂ O: 08.2; Found: 09.1 (M + H).

Example 26

Biological test

Cancer cells of human breast carcinoma (MDA-35), adapted to grow into solid cancer in the body of hairless mice, are injected with a cancer cell suspension of medium (3-5 × 10 ⁶ cells) into the fat pad of female hairless mice By implantation (taconic laboratories). Five mice in the group were used. When the cancer is large enough to be touched, that is, two to three weeks after cancer implantation, the cytotoxic compounds according to the invention are injected into the body of the animal by intravenous injection three times a week in MTD. The volume (size) of the cancer is measured with calipers every week while drug administration is withheld. The size of the cancer is calculated by the following equation, assuming the shape of the cancer is semi-elliptical:

Size = 1/2 (L / 2 × W / 2 × H) / 3Π

Where L = arm length, W = arm width, and H = arm height. During the analysis, the weight of the subject animal is measured and general health is examined. When the cancer reaches a diameter of about 15 mm (about 800 mm ³ ), is necrotic, or if the subject animal is killed, the animal is euthanized by carbon dioxide asphyxiation.

The size of the cancer in the animal body treated with the various cytotoxic compounds according to the invention was calculated and compared to the size of the cancer obtained from the animal treated with chlorobusyl (an anticancer agent comprising an aromatic nitrogen mustard). It was also compared to the size of cancers obtained from animals without drugs. As a result of investigation, the cytotoxic compound according to the present invention has been found to have a very excellent effect in preventing cancer growth.

Other configuration of the present invention

From the above description, those skilled in the art can identify the main features of the present invention, and various modifications of the present invention can be applied to various various conditions without departing from the scope of the present invention. For example, the conjugate system of a cytotoxic compound according to the present invention, even if a bond comprising a hetero atom, eg, -CH = N-CH ₂ -or -N = N-CH _2- , is not given above Can act as part of Therefore, such other configurations are also within the scope of the present invention.

Claims (45)

In the compound consisting of a fully active alkylation component comprising an electron withdrawing group, a bioreducing component comprising at least two double bonds, and a linker connecting the electroactive alkylation component and the bioreducing component, the bond Is a methylene group, a C ₃ hydrocarbon comprising one double bond or a C ₅ hydrocarbon comprising two alternating double bonds; The double bond of the bioreducing component is itself only when the bonder is a methylene group, and when the bonder is a C ₃ or C ₅ hydrocarbon, a conjugated system is formed together with the double bond included in the hydrocarbon to form the conjugate. When the reduction of the bioreduction component through the system allows electrons to move from the bioreduction component to the electron withdrawing of the electroactive alkylation component, thereby breaking the bond between the bonder and the electron withdrawing group, thereby the active alkylation component is active alkylation. A compound characterized by being able to be converted into a compound; Or salts of said compounds. The compound of claim 1, wherein the totally active alkylation component is an ester group, an urethane, or an aryl group substituted with a carbonate group and a bis (haloethyl) amino group; The positions remaining unsubstituted in the aryl group are each independently an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, an amino group, an aminoalkyl group, a hydroxy group, or a hydroxy group. Alkyl group, alkoxy group, oligoalkylene glycol, aryloxy group, aryloxy group, alkoxy group, heteroaryloxy group, heteroarkoxy group, ester group, amido group, aralkoxycarbonylamino group, ureido group (ureido ), A thio group, an alkylthio group, an arylthio group, an aralkylthio group, an ararylthio group, a heteroarylthio group, or a heteroaralkylthio group, wherein the compound is optionally substituted; Or salts of said compounds. The compound of claim 1, wherein the bioreduction component is converted into an alkylated compound by reduction; Or salts of said compounds. The compound according to claim 3, wherein the bioreduction component is quinone, and each of the quinone is independently an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, or a heteroaralkyl group at a non-oxo position of the quinone. ), Amino group, aminoalkyl group, hydroxy group, hydroxyalkyl group, alkoxy group, aryloxy group, aryloxy group, arlkoxy group, heteroaryloxy group, heteroarkoxy group, carboxylate, acyloxyalkyl group ( acyloxyalkyl), ester group, acyloxyalkyl group, amido group, amidoalkyl group, sulfoamido group, sulfonylamino group, thio group, alkylthio group, arylthio group, aralkylthio group, aralkylthio group, heteroaryl thi Or a heteroaralkylthio group is optionally substituted; If the substituent is substituted at the 2-C and 3-C positions or the 5-C and 6-C positions, the two substituents are optionally bonded to form an optionally substituted ring; Or salts of said compounds. A compound according to claim 4, wherein at each non-oxo position of the quinone, an alkyl group, an amino group, an aminoalkyl group, an alkoxy group, an acyloxyalkyl group, or a hydroxyalkyl group is optionally substituted; Or salts of said compounds. The compound according to claim 5, wherein the totally active alkylation component is a phenyl group in which an ester group and a bis (chloroethyl) amino group are substituted with each other in a meta or para position; The unsubstituted positions of the phenyl group are each independently an alkyl group, an alkoxy group, an oligoalkylene glycol, an aryloxy group, a heteroaryloxy group or a compound characterized in that the amino group is optionally substituted; Or salts of said compounds. The compound according to claim 6, wherein the phenyl group is substituted with an alkyl group, an alkoxy group, or an oligoalkylene glycol such that the bis (chloroethyl) amino group is in an ortho position; Or salts of said compounds. The compound of claim 4, wherein the substituent is substituted at the 2-C and 3-C positions or the 5-C and 6-C positions, and the two substituents combine to form an optionally substituted ring. compound; Or salts of said compounds. 9. The compound of claim 8, wherein the totally active alkylation component is a phenyl group in which an ester group and a bis (chloroethyl) amino group are substituted with each other in a meta or para position; The unsubstituted positions of the phenyl group are each independently an alkyl group, an alkoxy group, an oligoalkylene glycol, an aryloxy group, a heteroaryloxy group or a compound characterized in that the amino group is optionally substituted; Or salts of said compounds. The compound of claim 9, wherein the phenyl group is substituted with an alkyl group, an alkoxy group, or an oligoalkylene glycol such that the bis (chloroethyl) amino group is in an ortho position; Or salts of said compounds. The compound according to claim 4, wherein the totally active alkylation component is an ester group, a urethane, or a phenyl group substituted with a carbonate group and a bis (haloethyl) amino group; The positions remaining unsubstituted in the phenyl group are each independently an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, an amino group, an aminoalkyl group, a hydroxy group, or a hydroxyalkyl group. , Alkoxy group, oligoalkylene glycol, aryloxy group, aryloxy group, alkoxy group, heteroaryloxy group, heteroarkoxy group, ester group, amido group, aralkoxycarbonylamino group, ureido group (ureido) A compound characterized in that a thio, alkylthio group, arylthio group, aralkylthio group, heteroarylthio group, or heteroaralkylthio group is optionally substituted; Or salts of said compounds. 12. The compound of claim 11, wherein the bis (haloethyl) amino group is a bis (chloroethyl) amino group; Or salts of said compounds. 13. The compound of claim 12, wherein the phenyl group is substituted with an ester group; Or salts of said compounds. 14. The compound of claim 13, wherein the ester group is substituted with the bis (chloroethyl) amino group to be para or meta position; Or salts of the compounds. 15. The compound of claim 14, wherein the phenyl group includes an alkyl group, an aryl group, a heteroaryl group, an alkoxy group, an aryloxy group, a heteroaryloxy group, or an oligo alkylene glycol wherein the bis (chloroethyl) amino group and ortho position are used. A compound characterized in that it is substituted; Or salts of said compounds. The compound according to claim 1, wherein the totally active alkylation component is an ester group, urethane, or phenyl group substituted with a carbonate group and a bis (haloethyl) amino group; The positions remaining unsubstituted in the phenyl group are each independently an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, an amino group, an aminoalkyl group, a hydroxy group, or a hydroxyalkyl group. , Alkoxy group, oligoalkylene glycol, aryloxy group, aryloxy group, alkoxy group, heteroaryloxy group, heteroarkoxy group, ester group, amido group, aralkoxycarbonylamino group, ureido group (ureido) A compound characterized in that a thio, alkylthio group, arylthio group, aralkylthio group, heteroarylthio group, or heteroaralkylthio group is optionally substituted; Or salts of said compounds. 17. The compound of claim 16, wherein the phenyl group is a phenyl group substituted with an ester group and a bis (chloroethyl) amino group; The ester group is substituted with the bis (chloroethyl) amino group to be in a para or meta position; Or salts of said compounds. 18. The compound of claim 17, wherein the phenyl group includes an alkyl group, an aryl group, a heteroaryl group, an alkoxy group, an aryloxy group, a heteroaryloxy group, or an oligo alkylene glycol in which the bis (chloroethyl) amino group is ortho-positioned. A compound characterized in that it is substituted; Or salts of said compounds. The compound according to claim 18, wherein the bioreduction component is quinone, and each of the quinone is independently an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, or a heteroaralkyl group at a non-oxo position of the quinone. ), Amino group, aminoalkyl group, hydroxy group, hydroxyalkyl group, alkoxy group, aryloxy group, aryloxy group, alkoxy group, heteroaryloxy group, heteroarkoxy group, carboxylate, acyloxyalkyl group ( acyloxyalkyl), ester group, acyloxyalkyl group, amido group, amidoalkyl group, sulfoamido group, sulfonylamino group, thio group, alkylthio group, arylthio group, aralkylthio group, aralkylthio group, heteroaryl thi Or a heteroaralkylthio group is optionally substituted; If the substituent is substituted at the 2-C and 3-C positions or the 5-C and 6-C positions, the two substituents are optionally bonded to form an optionally substituted ring; Or salts of said compounds. 20. The compound of claim 19, wherein each non-oxo position of the quinone is independently an alkyl, amino, aminoalkyl, alkoxy, acyloxyalkyl or hydroxyalkyl group optionally substituted; Or salts of said compounds. 20. The compound of claim 19, wherein the substituent is substituted at the 2-C and 3-C positions or the 5-C and 6-C positions, and the two substituents combine to form an optionally substituted ring. compound; Or salts of said compounds. Quinone derivatives having the structure of: In the quinone derivatives, each of A, B, C, and D is independently -R^One, -R-NR^OneR², -O-R^One, -R-OH, -C (= O) O-R^One, -R-O-C (= O) R^One, -C (= O) -NR^OneR², -R-NR^One-C (= O) R², -SO₂-NR^OneR², -N = SO₂, -S-R^OneOr -L-W-Ph-N (CH₂CH₂X)₂ego; A, B is -L-W-Ph-N (CH₂CH₂X)₂If you do not belong to_,A and B may optionally form together with the quinone ring to form a fused ring of 5-6 atoms; C, D is -L-W-Ph-N (CH₂CH₂X)₂If you do not belong to_,C, D together with the quinone ring may form a Fused ring of 5-6 atoms; In the above, R is independently an alkyl group or may be erased; Each R^OneAnd R²Can independently be hydrogen, an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, or a heteroaralkyl group; Where L is-(CR³= CR⁴)_n-CR⁵R⁶Denoted by R³, R⁴, R⁵And R⁶Is independently hydrogen, alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group, or-(O-alkyl)_1-5ego; N may be 0, 1, or 2; W is -O-C (= O)-, -O-C (= O) -NR^One-Or -O-C (= 0) O-; Ph is a phenyl group, optionally an alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group, -R-NR^OneR², -OH,-(O-alkyl)_1-5, -O-aryl, -O-aralkyl, -O-heteroaryl, -O-heteroaralkyl, -R-OH, -C (= 0) O-R^One, -C (= O) -NR^OneR², -NR^One-C (= O) R², -NR^One-C (= O) O-R², -NR^One-C (= O) NR^OneR²Or -S-R^OneMay be substituted with; X is a halo group; If A and B do not form a ring fused with a quinone ring and C and D also do not form a ring fused with a quinone ring, then at least one of A, B, C, and D is -LW-Ph-N (CH ₂ CH ₂ X) ₂ ; Further, if none of A, B, C, or D is -LW-Ph-N (CH ₂ CH ₂ X) ₂ , then A and B or C and D form a fused ring with a quinone ring, and the formed fusion The ring has a double bond between two ring atoms, and one of the two ring atoms is substituted with -LW-Ph-N (CH ₂ CH ₂ X) ₂ , and the double bond is a double ring of the quinone ring. A quinone derivative, characterized in combination with a bond, to form a conjugated system capable of transferring electrons from one double bond to another double bond; Or salts thereof. 23. The quinone derivative of claim 22, wherein each of A, B, C, D is independently -R ¹ , -R-NR ¹ R ² , -OR ¹ , -ROC (= 0) R ¹ , or -R-OH Quinone derivatives, characterized in that selected from the group consisting of; Or salts thereof. The quinone derivative according to claim 23, wherein W is -O-C (= O)-, X is a chloro group, and n is 0; Or salts thereof. 25. A quinone derivative according to claim 24, wherein W and -N (CH ₂ CH ₂ X) ₂ are meta or para to each other; Or salts thereof. The quinone derivative of claim 25, wherein the phenyl group includes an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group,-(O-alkyl) _1-5 , -O-aryl, -O-aralkyl , -O-heteroaryl, or -O-heteroaralkyl group is a quinone derivative, characterized in that substituted with -N (CH ₂ CH ₂ X) ₂ and the ortho position; Or salts thereof. The quinone derivative of claim 22, wherein at least one of A, B, C, and D is -LW-Ph-N (CH ₂ CH ₂ X) ₂ ; Or salts thereof. 28. The quinone derivative of claim 27 wherein A and B, and C and D, both do not form a fused ring with a quinone ring, and only one of A, B, C, and D is -LW-Ph-N (CH ₂ CH). ₂ X) quinone derivative, characterized in that ₂ ; Or salts thereof. The quinone derivative of claim 28, wherein W is -OC (= 0)-, X is a chloro group, n is 0, and W and -N (CH ₂ CH ₂ X) ₂ are each meta or Substituted so as to be in the para position, the phenyl group is an alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group,-(O-alkyl) _1-5 , -O-aryl, -O-aralkyl, A quinone derivative characterized in that a -O-heteroaryl or an -O-heteroaralkyl group is substituted such that -N (CH ₂ CH ₂ X) _{2 is} in an ortho position; Or salts thereof. 23. A quinone derivative according to claim 22, wherein A and B, or C and D, form a fused ring with a quinone ring; Or salts thereof. The quinone derivative according to claim 30, wherein W is -O-C (= O)-, X is a chloro group, and n is 0; Or salts thereof. 32. A quinone derivative according to claim 31, wherein W and -N (CH ₂ CH ₂ X) ₂ are meta or para to each other; Or salts thereof. The quinone derivative of claim 32, wherein the phenyl group includes an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group,-(O-alkyl) _1-5 , -O-aryl, -O-aralkyl , -O-heteroaryl, or -O-heteroaralkyl group is a quinone derivative, characterized in that substituted with -N (CH ₂ CH ₂ X) ₂ and the ortho position; Or salts thereof. A quinone derivative according to claim 30, wherein none of A, B, C, and D is -LW-Ph-N (CH ₂ CH ₂ X) ₂ ; Or salts thereof. 35. The quinone derivative of claim 34, wherein W is -OC (= O)-, X is a chloro group, n is 0, and W and -N (CH ₂ CH ₂ X) ₂ are each meta or Substituted so as to be in the para position, the phenyl group is an alkyl group, alkenyl group, aryl group, aralkyl group, heteroaryl group, heteroaralkyl group,-(O-alkyl) _1-5 , -O-aryl, -O-aralkyl, A quinone derivative characterized in that a -O-heteroaryl or an -O-heteroaralkyl group is substituted such that -N (CH ₂ CH ₂ X) _{2 is} in an ortho position; Or salts thereof. The quinone derivative according to claim 2, wherein W is -O-C (= O)-, X is a chloro group, and n is 0; Or salts thereof. 37. A quinone derivative according to claim 36, wherein W and -N (CH ₂ CH ₂ X) ₂ are meta or para to each other; Or salts thereof. The quinone derivative of claim 37, wherein the phenyl group includes an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group,-(O-alkyl) _1-5 , -O-aryl, -O-aralkyl , -O-heteroaryl, or -O-heteroaralkyl group is a quinone derivative, characterized in that substituted with -N (CH ₂ CH ₂ X) ₂ and the ortho position; Or salts thereof. 39. The quinone derivative of claim 38, wherein each of A, B, C, D is independently -R ¹ , -R-NR ¹ R ² , -OR ¹ , -ROC (= 0) R ¹ , or -R-OH Quinone derivatives, characterized in that selected from the group consisting of; Or salts thereof. 40. A quinone derivative according to claim 39, wherein at least one of A, B, C, and D is -LW-Ph-N (CH ₂ CH ₂ X) ₂ ; Or salts thereof. The quinone derivative of claim 40 wherein A and B, and both C and D, do not form a fused ring with a quinone ring, and only one of A, B, C, and D is -LW-Ph-N (CH ₂ CH). ₂ X) quinone derivative, characterized in that ₂ ; Or salts thereof. 39. A quinone derivative according to claim 38, wherein A and B, or C and D, form a fused ring with a quinone ring; Or salts thereof. 43. A quinone derivative according to claim 42, wherein none of A, B, C and D is -LW-Ph-N (CH ₂ CH ₂ X) ₂ ; Or salts thereof. The quinone derivative of claim 22, wherein the quinone derivative has the structure 9 10 13 12 The quinone derivative of claim 22, wherein the quinone derivative has the structure 14 15 23