JPH10279549A - Quinone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having an electron-transmitting function in vitro. SOLUTION: A compound having a group of formula I [R<1> is imino, a group of the formula: CONH; R<2> is H, a halogen; (n) is 2-20], e.g. a naphthoquinone monomer compound of formula II. The compound having the group of formula I [(n) is 2; R<1> is imino group; a phospholipid is bound to the group] is obtained by adding 1,4-naphthoquinone, etc., to 3-aminopropionic acid dissolved in chloroform, dropping triethylamine on the mixture, distilling off the solvent, dissolving the residue in chloroform, adding N-hydroxysuccinimide and N,N'- dicyclohexylcarbodiimide, stirring, filtering, distilling off the solvent, dissolving the obtained succinimide compound in chloroform, adding the chloroform solution of dipalmitoylphosphatidylethanolamine, dropping trimethylamine on the mixture, and subsequently extracting with a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel quinone derivative.

[0002]

2. Description of the Related Art As organic compounds, those having a function of transferring each ion of anion and cation and an energy conversion function related thereto are known. For example, it is known that a relatively large number of natural and artificially synthesized derivatives having a porphine skeleton substituted with various groups have an electron or anion transfer function and an energy conversion function. .

[0003] On the other hand, quinone derivatives known as a group of dyes constituting a mitochondrial inner membrane or a photosynthetic membrane also act as an electron transfer medium in a living body, for example, energy conversion such as converting light energy into chemical energy. It is pointed out that it may have a function. However, although quinone derivatives have been mainly elucidated as an acceptor component for energy transfer, the details of the electron transfer behavior have not been elucidated. Also, as for the quinone derivative having the electron transfer behavior, only a few in vivo compounds such as ubiquinone (coenzyme Q), which is a hydrophobic coenzyme that transfers electrons between protein complexes, are known.

[0004]

SUMMARY OF THE INVENTION The present invention provides a novel quinone derivative having an electron transfer function even in a non-living body, particularly a naphthoquinone monomer compound and an anthraquinone monomer compound.

[0005]

Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies and found that one of the hydrogen atoms at the 2- and 3-positions of naphthoquinone and anthraquinone was added to an alkylene chain of an appropriate length. Or an imino group similarly substituted with a group represented by -CONH- to which an alkylene chain having an appropriate length has been added, or an imino group further having such an alkylene chain added thereto- A group represented by CONH- is naphthoquinone or anthraquinone substituted at any of the 2- and 3-positions, wherein a hydrogen atom which is not substituted at the 2- or 3-position is substituted with a halogen atom; Both naphthoquinone monomer compounds and anthraquinone monomer compounds composed of the constituent groups have been found to be novel quinone derivatives, and such derivatives have an electron transfer function. It was found that.

That is, the quinone derivative of the present invention has the general formula (3)

[0007]

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[In the formula (3), R ¹ represents an imino group or -C
Groups represented by ONH-, R ² represents a hydrogen or halogen atom, n represents an integer of 2 to 20. And a naphthoquinone monomer compound comprising a group represented by the formula:

The quinone derivative of the present invention has the general formula (4)

[0010]

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[In the formula (4), R ¹ represents an imino group or -C
Groups represented by ONH-, R ² represents a hydrogen or halogen atom, n represents an integer of 2 to 20. ] Anthraquinone monomer compound comprising a group represented by the formula:

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The quinone derivative in the present invention comprises:
A naphthoquinone monomer compound comprising a group represented by the general formula (3), wherein any one of hydrogens at positions 2 and 3 of 1,4-naphthoquinone is represented by an imino group or -CONH-. is the is substituted with a group (R ^1), further said imino group or -C
An alkylene chain of an appropriate length is bonded to a group represented by ONH-, that is, an alkylene group in which n is any integer from 2 to 20 in the general formula (3), and , hydrogen Write a group represented by the 3-position of the imino group or -CONH- not substituted are those substituted with either left or halogen atom of the hydrogen (R ^2). Examples of the naphthoquinone monomer compound having such a group include a compound in which -COOH is bonded to the group, and in particular, a compound in which lipid is bonded to the group and a compound in which metal is bonded to the group. preferable.

The quinone derivative according to the present invention is an anthraquinone monomer compound comprising a group represented by the general formula (4), wherein the group is a 2,3-position of 9,10-anthraquinone. Any of hydrogen is replaced with an imino group or -CONH-
Substituted with a group represented by (R ^1), further said imino group or -
An alkylene chain having an appropriate length bonded to the group represented by CONH-, that is, an alkylene group in which n is any integer from 2 to 20 in the general formula (4), and the anthraquinone 2 The hydrogen not substituted by the imino group at the 3-position or the group represented by -CONH- is hydrogen (R ² ), which is still hydrogen or substituted with a halogen atom. Examples of the anthraquinone monomer compound having such a group include a compound in which -COOH is bonded to the group, and a compound in which lipid is bonded to the group or a metal in which metal is bonded is preferable. Is preferred.

Each of the above quinone derivatives can be obtained by a known general synthesis process using a known compound such as a commercially available drug. That is, as the naphthoquinone monomer compound, for example, a group represented by the general formula (3) is represented by n
= 2, R ¹ is an imino group and the monomer compound is a phospholipid-bonded 1,2-naphthoquinone or 2,3-dihalogen-1,4 obtained by halogenating the compound. −
3-Aminopropionic acid in which naphthoquinone (halogen is chlorine, fluorine, bromine, or iodine) dissolved in chloroform is added, triethylamine is added dropwise, and the mixture is refluxed. N-Hydroxysuccinimide and N, N'-dicyclohexylcarbodiimide are added to the mixture, and the mixture is filtered with stirring, and the solvent is distilled off. The obtained succinimide compound was dissolved in chloroform, a chloroform solution of dipalmitoylphosphatidylethanolamine (DPPE) was added, trimethylamine was added dropwise, and the mixture was extracted with (C ₁₀ H _4).
Naphthoquinone monomer compound having a group represented by O ₂ ) H (NH)-(CH ₂ ) _2- : (C ₁₀ H ₄ O ₂ ) H (NH)
-(CH ₂ ) ₂ -DPPE or (C ₁₀ H ₄ O ₂ ) X (N
H) -Naphthoquinone monomer compound having a group represented by-(CH ₂ ) _2- where X is a halogen: (C ₁₀ H ₄ O ₂ )
_{X (NH) - (CH 2} ) can be obtained ₂ DPPE. When the product (solute) after solvent extraction is a mixture, it can be easily separated by a general separation operation, for example, column chromatography or the like.

Further, as a naphthoquinone monomer compound,
For example, when the group represented by the general formula (3) is such that n is 3 or more and 2
In the case of a monomer compound in which R ¹ is an imino group with an integer of 0 or less and the group is bonded to a phospholipid (DPPE), (n
+1) -Aminocarboxylic acid was added to 1,4-naphthoquinone or 2,3-dihalogen-1,4-naphthoquinone by the same synthesis method as described above to obtain (C ₁₀ H).
₄ O ₂ ) H (NH)-(CH ₂ ) _n-
naphthoquinone monomeric compounds having an integer of _{n = 3~20: (C 10 H} 4 O 2) H (NH) - (CH 2) n -DPP
E, or _{(C 10 H 4 O 2)} X (NH) - (CH 2) n - group represented by [where, X is a halogen, n = 3 to 20 integer]
Naphthoquinone monomer compound having: (C ₁₀ H ₄ O ₂ ) X
_{(NH) - (CH 2)} n -DPPE can be obtained.

Further, as the anthraquinone monomer compound, for example, a group represented by the general formula (4) wherein n is 2 and R ¹ is an imino group and the group is bonded to a phospholipid, In the case of the isomer compound, 9,10-anthraquinone or 2,3-dihalogen-9,10-anthraquinone (halogen is chlorine, fluorine, bromine or iodine) is dissolved in chloroform and dissolved in ethanol. -Aminopropionic acid was added, triethylamine was added dropwise, and the mixture was refluxed. The solvent was removed and the residue was dissolved in chloroform.
Hydroxysuccinimide and N, N'-dicyclohexylcarbodiimide are added, the mixture is stirred and filtered, and the solvent is distilled off. The obtained succinimide compound is dissolved in chloroform, and dipalmitoylphosphatidylethanolamine (DPP
Chloroform was added and E), by dropping reflux _{trimethylamine, (C 14 H 6 O 2} ) H (NH) -
(CH _{2) 2} - anthraquinone monomer compound having a group represented _{by: (C 14 H 6 O 2} ) H (NH) - (CH 2) 2 -D
PPE, or _{(C 14 H 6 O 2)} X (NH) - (CH 2) 2 -
A group represented by [where, X is halogen anthraquinone monomer compound _{having: (C 14 H 6 O 2} ) X (NH) - (C
H ₂ ) ₂ -DPPE can be obtained.

Further, as the anthraquinone monomer compound, for example, the group represented by the above general formula (4) is such that n is an integer of 3 or more and 20 or less and R ¹ is an imino group, and the group is combined with a phospholipid (DPPE ) Is a derivative obtained by adding (10) -anthraquinone or 2,3-dihalogen-9,10-anthraquinone to (n + 1) -aminocarboxylic acid of any length, the synthesis method similar to the _{above, (C 14 H 6 O 2} ) H (NH) - (CH 2) n - group represented by [where integer n = 3 to 20] anthraquinone monomeric compounds having a _{: (C 14 H 6 O 2} ) H (NH) -
(CH _{2) n} -DPPE, or _{(C 14 H 6 O 2)} X (NH)
-(CH ₂ ) _n-wherein X is a halogen, n
= Anthraquinone monomeric compounds having 3 to 20 _{integer]: (C 14 H 6 O} 2) X (NH) - (CH 2) n -DPPE
Can be obtained.

[0018]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail with reference to embodiments. Example 1 In a 300 ml three-necked flask, 2,3-
519.3 mg of dichloro-1,4-naphthoquinone (2.
29 mmol) and dissolved in 20 ml of chloroform. 136 mg (1.52 mmol) of 3-aminopropionic acid dissolved in 33 ml of a solution obtained by mixing 1 part by volume of water with 10 parts by volume of ethanol was gradually added thereto, and triethylamine was added dropwise. Minutes. The reaction solution was filtered, and the solvent was distilled off. The residue was dissolved again in 100 ml of chloroform and washed with distilled water. Then, silica gel chromatography (eluent:
Chloroform-chloroform / methanol = 40/1
(Represents a solution in which chloroform and methanol are mixed at a volume ratio of 40: 1. The product separated and purified by) is distilled off the solvent, dried in vacuo, and powdered naphthoquinone aminopropionate. I got This one
87 mg (0.310 mmo) in a 00 ml two-necked flask
l) and dissolved in 20 ml of chloroform. Then, 53.7 mg of N-hydroxysuccinimide (0.
466 mol) and 96.2 mg (0.466 mmol) of N, N'-dicyclohexylcarbodiimide (DCC)
After stirring at 0 ° C. for 1 hour, the reaction was carried out at room temperature for 11 hours. After adding 100 ml of chloroform thereto and filtering, the mixture was washed with distilled water and the organic phase was evaporated. To the obtained succinimide compound of naphthoquinone aminocaproate was added and dissolved 20 ml of chloroform, and dipalmitoylphosphatidylethanolamine (DPP) was added thereto.
E) 25 ml of a chloroform solution of 172 mg (0.249 mmol) was added, and several drops of triethylamine were added dropwise, and the mixture was reacted at room temperature for 20 hours. After the reaction, the solvent was distilled off and silica gel column chromatography (eluent: chloroform to chloroform / methanol = 40/1 to chloroform / methanol = 20/1 to chloroform / methanol = 9/1).
To chloroform / methanol = 4/1), and the final product was obtained by evaporating the solvent and drying under vacuum.

The final product is identified by a known analytical method such as ¹ H NMR spectrum, and the UV / vis absorption spectrum (medium: CHCl ₃ , CH ₂ Cl ₂ / EtOH =
Analysis of liposome solutions prepared with 9/1 and 0.01 M Bis-Tris buffer) indicated 236, 276, 4
Since the absorption was observed at 75 nm, the final product was a naphthoquinone monomer compound represented by the formula (5) bound to phospholipid (DPPE): (C ₆ H ₄ O ₂ ) Cl
It was confirmed to be (NH) (CH ₂ ) ₂ (DPPE). (Yield about 73.7%)

[0020]

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Next, a chloroform solution containing 100 μM of the naphthoquinone monomer compound was applied to an electrode area of 1 cm ^2.
Glassy carbon electrode (specific resistance about 60 × 10 ^-4 Ω
/ Cm) and dried in air at about 25 ° C for 15 minutes. Cyclic voltammetry of the naphthoquinone monomer compound on the lipid membrane was measured in a nitrogen stream at 25 ° C. The measurement was performed using Ag /
An AgCl electrode, a platinum electrode as a counter electrode, and a three-electrode cell comprising the above-mentioned glassy carbon electrode as a working electrode were used, and the potential width was periodically swept from 0.2 V to -0.8 V. As a result, a reversible electrode response of a naphthoquinone molecule having a formal potential of −0.46 V was observed, confirming that the present naphthoquinone monomer compound has an electron transfer function.

Example 2 2,3-Dichloro-1,4-naphthoquinone in a 300 ml three-necked flask 519.
3 mg (2.29 mmol) were added, and chloroform 20 was added.
was dissolved in ml. Ethanol / water = 10/1
(Volume ratio) After gradually adding 328 mg (1.52 mmol) of 12-aminododecanoic acid dissolved in 33 ml of the mixed solution, triethylamine was added dropwise and reacted at 60 ° C for 90 minutes. The reaction solution was filtered, and the solvent was distilled off. The residue was dissolved again in 100 ml of chloroform and washed with distilled water. Subsequently, silica gel chromatography (eluent: chloroform-chloroform / methanol = 40 /
The product was separated and purified according to 1), the solvent was distilled off, and the residue was dried under vacuum to obtain powdery naphthoquinone aminododecanoate. This was put in a 100 ml two-necked flask, and chloroform 20 was added.
was dissolved in ml. Next, 53.7 mg (0.466 mmol) of N-hydroxysuccinimide was added, and the mixture was stirred at 0 ° C. for 1 hour and reacted at room temperature for 11 hours. After adding 100 ml of chloroform thereto and filtering, the mixture was washed with distilled water and the organic phase was evaporated. To the obtained succinimide compound of naphthoquinone aminoundecanoate was added 20 ml of chloroform and dissolved. This is followed by dipalmitoyl phosphatidylethanolamine (DPPE) 172
mg (0.249 mmol) of chloroform solution 25m
1 was added, triethylamine was added dropwise, and the mixture was reacted at room temperature for 20 hours. After the reaction, after distilling off the solvent, silica gel column chromatography (eluent: chloroform-chloroform / methanol = 40/1 mixture-chloroform / methanol = 20 / 1-chloroform / methanol =
9/1 to chloroform / methanol = 4/1), and the solvent was distilled off and dried under vacuum to obtain a final product.

The final product was identified by the same analytical method as in Example 1 above. Among them, the UV / vis absorption spectrum analysis showed absorption at 237 nm and 276 nm. Naphthoquinone monomer compound represented by the formula (6): (C ₁₀ H ₄ O ₂ ) Cl (NH)
It was confirmed to be (CH ₂ ) ₁₁ (DPPE). (Yield about 56.9%)

[0024]

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Next, cyclic voltammetry of this naphthoquinone monomer compound in a nitrogen stream was measured in the same manner and under the same conditions as in Example 1. As a result, -0.4
Since a reversible electrode response of a naphthoquinone molecule having a formal potential of 3 V was observed, it was confirmed that the present naphthoquinone monomer compound has an electron transfer function.

Example 3 2,3-dichloro-9,10-anthraquinone 63 was placed in a 300 ml three-necked flask.
4.0 mg (2.30 mmol) was added and dissolved in 20 ml of chloroform. 178 mg of 4-aminopentanoic acid (1.51 mmol) dissolved in 33 ml of a solution obtained by mixing 1 part by volume of water with 10 parts by volume of ethanol.
l) was slowly added, and then triethylamine was added dropwise.
The reaction was performed at 65 ° C. for 90 minutes. The reaction solution was filtered, and the solvent was distilled off. The residue was dissolved again in 100 ml of chloroform and washed with distilled water. Next, the product separated and purified by silica gel chromatography (eluent: chloroform to chloroform / methanol = 40/1) was evaporated, and the residue was dried under vacuum to obtain powdery anthraquinone aminopentanoate. Put this in a 100 ml two-necked flask
1 mg (0.310 mmol), chloroform 20
was dissolved in ml. Next, 53.7 mg (0.466 mol) of N-hydroxysuccinimide and 96.2 mg of N, N′-dicyclohexylcarbodiimide (DCC).
(0.466 mmol), and the mixture was stirred at 0 ° C. for 1 hour, and then reacted at room temperature for 11 hours. After adding 100 ml of chloroform thereto and filtering, the mixture was washed with distilled water and the organic phase was evaporated. Chloroform 20 ml was added to the obtained succinimide compound of anthraquinone aminopentanoate.
Was added and dissolved, and 174 mg (0.250) of dipalmitoylphosphatidylethanolamine (DPPE) was added thereto.
(mmol) in 25 ml of a chloroform solution was added, and a few drops of triethylamine were added dropwise, followed by reaction at room temperature for 20 hours. After the reaction, the solvent was distilled off and silica gel column chromatography (eluent: chloroform-chloroform / methanol = 40)
/ 1-chloroform / methanol = 20/1-chloroform / methanol = 9/1-chloroform / methanol = 4/1), and the solvent was distilled off and dried under vacuum to obtain the final product.

The final product was identified by the same analysis method as in Example 1 above. Among them, the UV / vis absorption spectrum analysis showed absorption at 258 nm and 329 nm. An anthraquinone monomer compound represented by the formula (7): (C ₁₄ H ₆ O ₂ ) Cl (N
H) (CH ₂ ) ₄ (DPPE).
(Yield about 45.3%)

[0028]

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Next, cyclic voltammetry of this anthraquinone monomer compound in a nitrogen stream was measured in the same manner and under the same conditions as in Example 1. As a result, -0.
Since a reversible electrode response of an anthraquinone molecule having a formal potential of 49 V was observed, it was confirmed that the present anthraquinone monomer compound has an electron transfer function.

Example 4 100 m of 9,10-anthraquinone-2-carboxylic acid was placed in a 50 ml two-necked flask.
g (0.397 mmol) was added, suspended in 20 ml of benzene, and refluxed for 30 minutes. 8.7 of thionyl chloride
ml (0.119 mmol), reflux for 9 hours,
Further, 50 ml of benzene was added, and the solvent distillation was repeated until the thionyl chloride odor disappeared. Add ethanol 10
177 mg of 4-aminopentanoic acid dissolved in 33 ml of a solution obtained by mixing 1 part by volume of water with respect to 1 part by volume (1.50 m
mol)), triethylamine was added dropwise, and the mixture was reacted at 65 ° C. for 90 minutes. The reaction solution was filtered, and the solvent was distilled off. The residue was dissolved again in 100 ml of chloroform and washed with distilled water. Then, silica gel chromatography (eluent: chloroform-chloroform /
The product separated and purified using methanol = 40/1) was evaporated, and the residue was dried under vacuum to obtain powdery anthraquinone carbamoylpentanoate. 110 mg (0.310 mmol) of this was placed in a 100 ml two-necked flask, and dissolved in 20 ml of chloroform. Then, 53.7 mg (0.466 mol) of N-hydroxysuccinimide and N, N′-dicyclohexylcarbodiimide (DCC)
96.2 mg (0.466 mmol) was added, and at 0 ° C., 1
After stirring for an hour, the reaction was performed at room temperature for 11 hours. After adding 100 ml of chloroform thereto and filtering, the mixture was washed with distilled water and the organic phase was evaporated. 20 ml of chloroform was added to the obtained succinimide compound of anthraquinone aminopentanoate and dissolved, and 175 mg of dipalmitoylphosphatidylethanolamine (DPPE) was added thereto.
(0.250 mmol) of a chloroform solution (25 ml) was added, and a few drops of triethylamine were added dropwise, followed by reaction at room temperature for 20 hours. After the reaction, the solvent was distilled off and silica gel column chromatography (eluent: chloroform to chloroform / methanol = 40/1 to chloroform / methanol = 20 /
1 / chloroform / methanol = 9/1 to chloroform / methanol = 4/1).
The final product was obtained by vacuum drying.

The final product was identified by the same analysis method as in Example 1 above. Among them, UV / vis absorption spectrum analysis showed absorption at 258 nm and 329 nm. Anthraquinone monomer compound represented by formula (8): (C ₁₄ H ₆ O ₂ ) H (CON
H) (CH ₂ ) ₄ (DPPE).
(Yield about 47.1%)

[0032]

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Next, cyclic voltammetry of this anthraquinone monomer compound in a nitrogen stream was measured in the same manner and under the same conditions as in Example 1. As a result, -0.
Since a reversible electrode response of an anthraquinone molecule having a formal potential of 51 V was observed, it was confirmed that the present anthraquinone monomer compound has an electron transfer function.

[0034]

The novel quinone derivative of the present invention is a monomer compound having an excellent electron transfer function not only in a solution system but also in an air stream. Such a quinone derivative may be sufficiently applicable as an energy conversion member that can be used in a daily environment such as the atmosphere.

Claims (2)

[Claims] 1. A compound of the general formula (1) [In the formula (1), R ¹ is an imino group or a group represented by —CONH—, R ² is a hydrogen or halogen atom, and n is 2 to 2
Represents an integer of 0. ] The quinone derivative characterized by the naphthoquinone monomer compound which consists of a group shown by these. 2. A compound of the general formula (2) [In the formula (2), R ¹ is an imino group or a group represented by —CONH—, R ² is a hydrogen or halogen atom, and n is 2 to 2.
Represents an integer of 0. ] The quinone derivative characterized by the anthraquinone monomer compound which consists of a group shown by these.