JP2008222626A - Porphyrin compound having acyl group at 2-position, albumin-porphyrin composite and artificial oxygen-carrier - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a porphyrin compound effectively functioning as an artificial oxygen-carrier by a more simple method. <P>SOLUTION: The porphyrin compound has an acyl group at the 2-position. The albumin-porphyrin composite comprises albumin and the porphyrin compound clathrated therein. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a porphyrin compound that can be used as an active center of an artificial oxygen carrier capable of reversibly binding and dissociating oxygen, and in particular, a porphyrin compound having an acyl group at the 2-position, an albumin-porphyrin complex containing the same, and an artificial It relates to an oxygen carrier.

  Hemoglobin, which efficiently transports oxygen from the lungs to peripheral tissues in vivo, and myoglobin, which is widely distributed in muscle tissue and plays a role in oxygen storage, is heme, a porphyrin iron (II) complex. The oxygen molecule is reversibly bound and dissociated from its central iron (II) in an end-on form. Attempts to synthetically reproduce porphyrin iron (II) complexes having oxygen adsorption / desorption functions similar to heme have been active since the late 1970s, and many derivatives have been reported so far. (For example, non-patent documents 1 and 2 are given as an initial example). The research group of the inventors of the present application pays attention to the surrounding molecular environment of heme (the so-called heme pocket) inside hemoglobin, and in order to form a stable oxygen complex by the porphyrin iron (II) complex, (i) porphyrin Four hydrophobic substituents are arranged on the oxygen coordination seat side of the plane to prevent the formation of μ-oxo dimer, and (ii) a basic axial arrangement necessary for effectively exhibiting oxygen binding ability Considering that it is essential to introduce a ligand, such as an imidazolylalkyl group, into the porphyrin ring at the 2-position by a covalent bond, a group of 2-imidazolylalkyl-5,10,15,20 tetrakis (α, α, α, α -O-Substituted amide) phenylporphyrin iron (II) complex was synthesized precisely (Patent Documents 1 and 2, Non-Patent Documents 3 and 4). These porphyrin iron (II) complexes can form extremely stable oxygen complexes at room temperature in solvents such as toluene, benzene, dichloromethane, dimethylformamide and the like. However, in order to use it as an artificial oxygen carrier, water must be used as a solvent (dispersion medium). In general, in water, protons are added to coordinated oxygen, and central iron (II) undergoes irreversible oxidation, making it difficult to obtain a stable oxygen-coordinated porphyrin metal complex. Our research group encapsulates the above porphyrin iron (II) complex in a liposomal bilayer membrane, in a lipid droplet of lipid microspheres, or in a hydrophobic domain of human serum albumin. As a result, the inventors succeeded in developing an artificial oxygen carrier that can reversibly absorb and desorb oxygen even under physiological conditions (water, pH 7.4, 37 ° C.) (Patent Documents 2, 3, and 4).

On the other hand, in order to use these porphyrin iron (II) complexes as active centers of artificial oxygen carriers widely in the medical, pharmaceutical and industrial fields, it is necessary to establish a system capable of mass production by a simple method. Needless to say. However, the most important synthesis step of this compound, that is, the process of covalently introducing an imidazolylalkyl group into the 2-position of the porphyrin ring, includes (i) first inserting copper into the porphyrin, and (ii) 2 by Vilsmeier reaction. After constructing one formyl group at the position, (iii) elimination of the central copper, (iv) reduction of the formyl group to a hydroxymethyl group, and (v) final imidazolylalkylcarboxylic acid binding, a total of five steps Operation.
JP-A-6-271777 JP 2003-40893 A JP-A-8-201873 JP 2006-45173 A JP Collman, Acc. Chem. Res., 10, 265 (1977) F. Basolo, BM Hoffman, JA Ibers, Acc. Chem. Res., 8, 384 (1975) E. Tsuchida, T. Komatsu, S. Kumamoto, K. Ando, H. Nishide, J. Chem. Soc. Perkin. Trans. 2, 747 (1995) T. Komatsu, Y. Matsukawa, E. Tsuchida, Bioconjugate Chem., 13, 397 (2002)

  The present invention has been made in view of the circumstances as described above, solves the problems of the prior art, and provides a porphyrin compound that can effectively act as an artificial oxygen carrier by a simpler method. And That is, it is an object to establish a method for activating the porphyrin ring 2-position and introducing an imidazolylalkyl group or histidyl group acting as an axial base by a covalent bond with a smaller number of synthesis steps.

  As a result of intensive studies on molecular design and functional expression of substituted porphyrin compounds, the present inventors have changed the ω-carboxyl alkanoyl group to 2,10,15,20-tetrakis (o-substituted amidophenyl) porphyrin compound 2- A porphyrin compound having a chemical structure and function equivalent to conventional ones and capable of being synthesized with a minimum number of steps can be obtained by directly introducing a terminal carbonyl group and a histidyl group or an imidazolylalkyl group in one step. The present invention has been found out and can be completed. Conventionally, in order to introduce an axial base ligand at the 2-position of the porphyrin ring, a total of five stages of reaction was necessary, but according to the method of the present invention, it can be achieved in two stages.

  That is, according to the present invention, a porphyrin compound having an acyl group at the 2-position is provided.

According to a first more specific aspect of the present invention, the general formula [I]:

(Here, R ₁ is a linear or alicyclic hydrocarbon group which may have a substituent, R ₂ is an alkylene group, R ₃ is an α-amino acid, or two α-amino acids. Dipeptide, R ₄ is a hydroxyl group, an alkyloxy group, a t-butyloxy group or a benzyloxy group, R ₅ is a hydrogen atom or a methyl group, and M is bonded to two pyrrole nitrogens out of four pyrrole nitrogens in the porphyrin ring. 2 hydrogen atoms, or transition metal ions in the 4th to 5th periods, X ⁻ represents a halide ion, and n represents the number of X ⁻ represents the number obtained by subtracting 2 from the valence of the metal ion M) The porphyrin compounds shown are provided.

According to a second more specific aspect of the present invention, the general formula [II]:

(Here, R ₆ is a linear or alicyclic hydrocarbon group which may have a substituent, R ₇ is an alkylene group, R ₈ is an α-amino acid or two α-amino acids. Dipeptide, R ₉ is a hydroxyl group, an alkyloxy group, a t-butyloxy group or a benzyloxy group, M is two hydrogen atoms bonded to two pyrrole nitrogens among the four pyrrole nitrogens in the porphyrin ring, or A transition metal ion of five periods, X ⁻ represents a halide ion, and n represents the number of X ⁻ represents a number obtained by subtracting 2 from the valence of the metal ion.

Furthermore, according to a third more specific aspect of the present invention, the general formula [III]:

(Where R ₁₀ is a linear or alicyclic hydrocarbon group which may have a substituent, R ₁₁ is an alkylene group, R ₁₂ is an alkyleneamino group or alkyleneoxy group, and R ₁₃ is a hydrogen atom. M is a methyl group or an alkylene group, M is two hydrogen atoms bonded to two pyrrole nitrogens among the four pyrrole nitrogens in the porphyrin ring, or a transition metal ion in the 4th to 5th periods, and X ⁻ is a halide ion. Wherein n represents the number of X ⁻ represents a number obtained by subtracting 2 from the valence of the metal ion.

  Furthermore, the present invention provides an albumin-porphyrin complex formed by inclusion of the porphyrin compound of the present invention in albumin.

  Furthermore, the present invention provides a surface-modified albumin-porphyrin obtained by covalently bonding a poly (ethylene glycol) chain to the albumin-porphyrin complex of the present invention so that the average number of binding molecules per albumin molecule is 1-15. Provide a complex.

  In addition, the present invention provides an artificial oxygen carrier containing the albumin-porphyrin complex of the present invention.

  According to the present invention, a porphyrin compound that can be easily synthesized and can form a stable oxygen complex is provided. This compound has a histidyl group or imidazolylalkyl group functioning as a basic axial ligand at the 2-position via an acyl bond, and exhibits excellent oxygen binding properties, as well as an artificial oxygen carrier, gas adsorption It effectively acts as an agent, an oxygen adsorption / desorption agent, a redox catalyst, an oxygen oxidation reaction catalyst, and the like.

  The porphyrin compound of the present invention has an acyl group at the 2-position, and more specifically, those represented by the above formula [I], [II] or [III] are preferred.

In the general formula [I], R ₁ is a linear or alicyclic hydrocarbon group which may have a substituent. R ₁ is preferably a linear or alicyclic hydrocarbon group having a substituent at the 1-position. Examples of such linear or alicyclic hydrocarbon groups include 1,1-disubstituted C ₁ -C ₁₀ alkyl groups, 1-substituted cyclopropyl groups, 1-substituted cyclopentyl groups, 1-substituted cyclohexyl groups. , 2-substituted norbornyl groups (the substituents in these groups are methyl group, alkylamide group (R′CONH—), alkyl ester group (R′OOC—) or alkyl ether group (R′O—)), 1- A methyl-2-cyclohexenyl group, or a 1-adamantyl group. Here, the alkyl group represented by R ′ is preferably a C _{1 to} C ₆ alkyl group.

In the general formula [I], R ₂ is an alkylene group, preferably a C _{2 to} C ₄ alkylene group.

In the general formula [I], R ₃ is an α-amino acid or a dipeptide composed of two α-amino acids, preferably an α-amino acid having a hydrophobic residue or an α-amino acid having a hydrophobic residue It is a dipeptide composed of two. Examples of such α-amino acids are isoleucine, leucine, phenylalanine, valine, alanine, glycine and the like.

In the general formula [I], R ₄ is a hydroxyl group, an alkyloxy group, a t-butyloxy group, or a benzyloxy group. The alkyl chain length of the alkyloxy group is preferably C _{1 to} C ₁₀ .

In the general formula [I], R ₅ is a hydrogen atom or a methyl group.

In the general formula [I], M is two hydrogen atoms bonded to two pyrrole nitrogens among the four pyrrole nitrogens in the porphyrin ring, or a central transition metal ion (a transition metal ion in the fourth to fifth periods of the periodic table). is there. X ⁻ represents a halide ion such as a chloride ion or a bromide ion, and the number n of X ⁻ is a value obtained by subtracting 2 from the valence of the transition metal ion M.

In the general formula [II], R ₆ is a linear or alicyclic hydrocarbon group which may have a substituent. R ₆ is preferably a linear or alicyclic hydrocarbon group having a substituent at the 1-position. Examples of such linear or alicyclic hydrocarbon groups include 1,1-disubstituted C ₁ -C ₁₀ alkyl groups, 1-substituted cyclopropyl groups, 1-substituted cyclopentyl groups, 1-substituted cyclohexyl groups. , 2-substituted norbornyl groups (the substituents in these groups are methyl group, alkylamide group (R′CONH—), alkyl ester group (R′OOC—) or alkyl ether group (R′O—)), 1- A methyl-2-cyclohexenyl group, or a 1-adamantyl group. Here, the alkyl group represented by R ′ is preferably a C _{1 to} C ₆ alkyl group.

In the general formula [II], R ₇ is an alkylene group, preferably a C _{2 to} C ₄ alkylene group.

In the general formula [II], R ₈ is an α-amino acid or a dipeptide composed of two α-amino acids, preferably an α-amino acid having a hydrophobic residue or an α-amino acid having a hydrophobic residue It is a dipeptide composed of two. Examples of such α-amino acids are isoleucine, leucine, phenylalanine, valine, alanine, glycine and the like.

In the general formula [II], R ₉ is a hydroxyl group, an alkyloxy group, a t-butyloxy group, or a benzyloxy group. The alkyl chain length of the alkyloxy group is preferably C _{1 to} C ₁₀ .

In the general formula [II], M is two hydrogen atoms bonded to two pyrrole nitrogens among the four pyrrole nitrogens in the porphyrin ring, or a central transition metal ion (a transition metal ion in the fourth to fifth periods of the periodic table). is there. X ⁻ represents a halide ion such as a chloride ion or a bromide ion, and the number n of X ⁻ is a value obtained by subtracting 2 from the valence of the transition metal ion M.

In the general formula [III], R ₁₀ is a linear or alicyclic hydrocarbon group which may have a substituent. R ₁₀ is preferably a linear or alicyclic hydrocarbon group having a substituent at the 1-position. Examples of such linear or alicyclic hydrocarbon groups include 1,1-disubstituted C ₁ -C ₁₀ alkyl groups, 1-substituted cyclopropyl groups, 1-substituted cyclopentyl groups, 1-substituted cyclohexyl groups. , 2-substituted norbornyl groups (the substituents in these groups are methyl group, alkylamide group (R′CONH—), alkyl ester group (R′OOC—) or alkyl ether group (R′O—)), 1- A methyl-2-cyclohexenyl group, or a 1-adamantyl group. Here, the alkyl group represented by R ′ is preferably a C _{1 to} C ₆ alkyl group.

In the general formula [III], R ₁₁ is an alkylene group, preferably a C ₂ -C ₄ alkylene group.

In the general formula [III], R ₁₂ is alkylene amino group or alkyleneoxy group, preferably a C ₄ -C ₁₀ alkylene amide or C ₄ -C ₁₀ alkylene oxycarbonyl group.

In the general formula [III], R ₁₃ is a hydrogen atom, a methyl group or an alkylene group, and the alkyl chain length of the alkylene group is preferably C _{1 to} C ₁₀ .

In the general formula [III], M is two hydrogen atoms bonded to two pyrrole nitrogens among the four pyrrole nitrogens in the porphyrin ring, or a central transition metal ion (a transition metal ion in the fourth to fifth periods of the periodic table). is there. X ⁻ represents a halide ion such as a chloride ion or a bromide ion, and the number n of X ⁻ is a value obtained by subtracting 2 from the valence of the transition metal ion M.

  In the general formula [III], when M is a transition metal ion of the 4th to 5th periods such as Co and Fe, the histidyl group or the imidazolyl group introduced into the porphyrin 2 position can be coordinated in the molecule. . Such a porphyrin compound can exhibit an oxygen binding ability only by the molecule.

  From the above, the porphyrin compound of the present invention effectively introduces an axial base ligand necessary for oxygen coordination into the porphyrin ring 2 position via an acyl bond and acts effectively as an active center of the artificial oxygen carrier.

  The porphyrin compound also acts as a catalyst for redox reaction, oxygen oxidation reaction, and oxygen addition reaction. Therefore, the porphyrin compound of the present invention can be used not only as an artificial oxygen carrier but also as a gas adsorbent, a redox catalyst, an oxygen oxidation reaction catalyst, and an oxygen addition reaction catalyst.

The porphyrin compound as described above may be produced by any method. For example, the following general formula [IV]:

5,10,15,20-tetrakis (α, α, α, α-o-aminophenyl) porphyrin can be synthesized as a starting material.

  Specifically, first, 5,10,15,20-tetrakis (α, α, α, α-o) obtained according to the method described in T. Komatsu et al., Bioconjugate Chem., 13, 397 (2002). -Substituted amidophenyl) porphyrin A ω-carboxylalkanoyl group is introduced into copper (II). The introduction can be achieved, for example, by the following method.

  5,10,15,20-tetrakis (α, α, α, α-o-substituted amidophenyl) porphyrin copper (II) is dissolved in a suitable dry organic solvent (for example, dichloromethane, chloroform, etc.) to form a cyclic dicarboxylic acid. An anhydride (for example, glutaric anhydride, etc.) and aluminum chloride are added and refluxed at the boiling point for 10 to 24 hours under a nitrogen atmosphere. This is dropped into an acidic aqueous solution, extracted with an organic solvent such as chloroform, dried, and then fractionally purified by silica gel column chromatography. In this way, 2- (carboxyalkanoyl) -5,10,15,20-tetrakis (α, α, α, α-o-substituted amidophenyl) porphyrin copper (II) is obtained.

  The 2- (carboxyalkanoyl) -5,10,15,20-tetrakis (α, α, α, α-o-substituted amidophenyl) porphyrin copper (II) is dissolved in a suitable organic solvent (for example, dichloromethane), concentrated. When sulfuric acid is added and vigorously stirred at room temperature for 10 minutes, the color of the solution turns green. This solution is dropped into a two-layer solution of chloroform and ice water, neutralized with sodium carbonate, the chloroform layer is washed several times with pure water, extracted, washed with water, dehydrated, dried, and then subjected to silica gel column chromatography. To fractionate and purify. Thus, 2- (carboxyalkanoyl) -5,10,15,20-tetrakis (α, α, α, α-o-substituted amidophenyl) porphyrin is obtained.

  This 2- (carboxyalkanoyl) -5,10,15,20-tetrakis (α, α, α, α-o-substituted amidophenyl) porphyrin and triethylamine are dissolved in anhydrous dimethylformamide and purged with nitrogen for 10 to 30 minutes. . Add the coupling reagent benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphoric acid (BOP) and stir for 10-30 minutes under nitrogen atmosphere. Thereafter, an imidazole or histidine derivative having a hydroxyl group or an amino group is added, and the mixture is stirred at room temperature for 10 to 18 hours under light shielding in a nitrogen atmosphere. After confirming the progress of the reaction by TLC, it is dropped into pure water, and the porphyrin is collected by precipitation, dissolved in an appropriate organic solvent (for example, chloroform) and collected. After drying this over anhydrous sodium sulfate, the solvent is removed under reduced pressure and fractionated and purified by silica gel column chromatography. Thus, the desired product 2- (substituted imidazolyl) alkanoyl) -5,10,15,20-tetrakis (α, α, α, α-o-substituted amidophenyl) porphyrin is obtained.

  In this product, since the imidazole ring site is decomposed by singlet oxygen, the purification operation is preferably performed in a dark place.

  Introduction of the central metal into the porphyrin thus obtained is achieved by a general method described in, for example, D. Dolphin ed., The Porphyrin, 1978, Academic Press, and is obtained as a corresponding porphyrin compound. Generally, a porphyrin iron (III) complex is obtained in the case of an iron complex, and a porphyrin cobalt (II) complex is obtained in the case of a cobalt complex.

  In the case of the iron (III) complex among the above porphyrin compounds, an appropriate reducing agent (sodium dithionite, ascorbic acid, etc.) is used, and the central metal is changed from trivalent to divalent by a conventional method. If reduced, oxygen binding activity can be imparted.

  The iron (II) complex of the porphyrin compound of the present invention can be used for the hydrophobic properties of bilayer membranes of phospholipid liposomes, lipid droplets of lipid microspheres, or human serum albumin, recombinant human serum albumin, or albumin multimers. It may be included in a domain. Even in these embedded materials and composites, the porphyrin iron (II) complex can adsorb and desorb oxygen according to the oxygen partial pressure. That is, such oxygen bond dissociation can be repeatedly performed reversibly, and the porphyrin compound of the present invention effectively acts as an oxygen adsorbing / desorbing agent or an artificial oxygen carrier.

  In addition, the porphyrin compound as described above is not limited to oxygen as long as it is a gas capable of coordinating to a metal, and, for example, carbon monoxide, nitrogen monoxide, nitrogen dioxide, and the like can be bonded. Therefore, the porphyrin compound of the present invention can also be applied as a redox reaction catalyst or gas adsorbent in homogeneous and heterogeneous systems.

  EXAMPLES Next, although an Example demonstrates this invention, this invention is not limited by these Examples.

<Example 1>
5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin copper in chloroform solution (40 mL) of glutaric anhydride (554 mg; 4.9 mmol) (II) (300 mg; 0.24 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Aluminum chloride (646 mg; 4.9 mmol) was added thereto, and the mixture was stirred at room temperature for 15 minutes and then stirred at 35 ° C. for 24 hours. The obtained solution was added dropwise to 300 mL of 2N HCl aqueous solution under ice cooling and stirred for 30 minutes. This was extracted with chloroform, washed several times with pure water, dried over anhydrous sodium sulfate, filtered, and then the solvent was removed under reduced pressure. The obtained residue was fractionated and purified by a silica gel column (chloroform / methanol: 10/1 (volume / volume)), and the target product was collected and dried in vacuum. Thus, reddish brown 2- (4-carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin copper (II ) Was obtained in a yield of 33 mg (yield 10%).

  Of the obtained 2- (4-carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin copper (II) The analysis results were as follows.

Thin layer chromatography (chloroform / methanol: 10/1 (volume / volume): Rf: 0.62 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1686 (ν _{C = O} (amide, ketone)), 1728 (ν _{C = O} (carboxylic acid))
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 421, 543, 581, 649, 688 nm)
FAB-MS spectrum (m / z): 1347 ([M + H] ⁺ ).

<Example 2>
2- (4-Carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin copper obtained in Example 1 ( II) 1 mL of sulfuric acid was added to a dichloromethane solution (2 mL) of (30 mg; 22 μmol), and the mixture was stirred at room temperature for 15 minutes. This was dropped into 20 mL of ice water, the pH of the solution was adjusted to 7 using sodium hydrogen carbonate, and extracted with chloroform. The product was fractionated and purified using a silica gel column (chloroform / methanol: 10/1 (volume / volume)), and the target product was collected and dried in vacuo. Thus, reddish brown 2- (4-carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin was obtained in a yield of 22 mg ( (Yield 75%).

  The analysis results of 2- (4-carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin are as follows: Met.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.54 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1682 (ν _{C = O} (amide, ketone)), 1728 (ν _{C = O} (carboxylic acid)), 3428 (ν _NH )
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 425, 520, 555, 595, 653 nm)
FAB-MS spectrum (m / z): 1286 ([M + H] ⁺ ).

¹ H-NMR spectrum (CD ₂ Cl ₂ ; δ (ppm)): δ = −2.6 (s, 2H, inner H), 0.1-1.0 (m, 52H, 1-methylcyclohexanoylamino), 1.6-1.8 ( M , 2H, -C H ₂ CH ₂ COOH), 2.3 (m, 2H, -C H ₂ COOH), 2.8-3.2 (m, 2H, -C H ₂ (CH ₂ ) ₂ COOH), 7.0 (s , 1H, amide), 7.3-8.0 (m, 15H, amide and phenyl), 8.2 (d, 1H, phenyl), 8.5-8.7 (d, 3H, phenyl), 8.7-8.9 (m, 7H, pyrrole-β ).

<Example 3>
2- (4-Carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin obtained in Example 2 (22 mg 17 μmol), glycyl-L-histidine methyl ester (16 mg; 68 μmol), benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (113 mg; 68 μmol), dimethylformamide (3 mL), triethylamine ( 10 μL) was added and stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, washed with pure water, and extracted with chloroform. This was fractionated and purified by a silica gel column (chloroform / methanol: 8/1 (volume / volume)), and the target product was collected and dried in vacuo. Thus, reddish brown 2- (4-((o-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexene). Sanoylamino) phenyl) porphyrin was obtained in a yield of 11 mg (43% yield).

  2- (4-((o-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) The analysis results of phenyl) porphyrin were as follows.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.47 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1682 (ν _{C = O} (amide, ketone)), 1741 (ν _{C = O} (ester)), 3426 (ν _NH )
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 426, 520, 555, 595, 653 nm)
FAB-MS spectrum (m / z): 1494 ([M + H] ⁺ ).

¹ H-NMR spectrum (CD ₂ Cl ₂ ; δ (ppm)): -2.6 (s, 2H, inner H), 0.1-1.0 (m, 52H, 1-methylcyclohexaneamide), 1.8-2.0 (m, 2H , -C H ₂ CH ₂ CONH-), 2.2 (m, 2H, -C H ₂ CONH-), 2.8-3.2 (m, 2H, -C H ₂ (CH ₂ ) ₂ CONH-), 3.2 (m, 2H, -C H ₂ -imidazole)), 3.6 (m, 3H, -OCH ₃ ), 3.9 (m, 2H, -NHC H ₂ CO-), 4.8 (br, 1H, -NHC H (CH ₂ Im) CO-), 6.7-6.9 (m, 2H, amide and imidazole (Im)), 7.3 (m, 1H, phenyl), 7.4 (m, 2H, amide and Im), 7.5 -8.0 (m, 11H, Phenyl), 8.1 (s, 1H, amide), 8.3-8.4 (m, 3H, phenyl), 8.6 (d, 1H, phenyl), 8.7-8.9 (m, 7H, pyrrole-β).

<Example 4>
The iron introduction reaction to porphyrin can be achieved by a general method described in, for example, D. Dolphin, The Porphyrin, 1978, Academic Press.

  2 mL of 47% hydrobromic acid aqueous solution was sufficiently degassed and deoxygenated, then 21 mg of electrolytic iron was quickly added, and the temperature was raised to 80 ° C. and stirred for 1 hour. The color of the solution changed from colorless and transparent to light green. When the electrolytic iron was completely dissolved, the temperature was raised to 130 ° C., and hydrobromic acid and water were evaporated to obtain white solid ferrous bromide. Next, 2- (4-((O-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- ( 1-methylcyclohexanoylamino) phenyl) porphyrin (11 mg; 7.4 μmol), 2,6-lutidine (13 μL; 110 μmol) of tetrahydrafuran solution 10 mL prepared was added dropwise to ferrous bromide in a nitrogen atmosphere, Reflux at boiling for 2 hours. After removing the solvent under reduced pressure, this was extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Fractionation and purification were performed on a silica gel column (chloroform / methanol (8/1) (volume / volume)), and the target product was collected and dried in vacuo. Thus, 2- (4-((o-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoyl) Amino) phenyl) porphyrin iron (III) bromide was obtained in a yield of 10 mg (88% yield).

  The resulting 2- (4-((o-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexa) The analysis results of noylamino) phenyl) porphyrin iron (III) bromide were as follows.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.38 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1690 (ν _{C = O} (amide, ketone)), 1741 (ν _{C = O} (ester))
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 344, 423, 583 nm)
FAB-MS spectrum (m / z): 1547 ([M-Br] ⁺ ).

<Example 5>
In Example 1, instead of 5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin copper (II), 5,10,15, 20-tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin copper (II), succinic anhydride instead of glutaric anhydride, 2- (3-carboxypropanoyl) -5, 10,15,20-Tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin copper (II) was synthesized.

  The analysis results of the obtained 2- (3-carboxypropanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin copper (II) are as follows: It was as follows.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.3 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1687 (ν _{C = O} (amide, ketone)), 1728 (ν _{C = O} (carboxylic acid))
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 416, 537, 575, 642, 682 nm).

FAB-MS spectrum (m / z): 1172 ([M + H] ⁺ ).

<Example 6>
In Example 2, 2- (4-carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin copper (II) Instead of 2- (3-carboxypropanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin copper (II) obtained in Example 5. Using this, 2- (3-carboxypropanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin was synthesized.

  The analysis results of the obtained 2- (3-carboxypropanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin were as follows. .

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.26 (monospot))
Infrared absorption spectrum (cm ⁻¹ ): 1683 (ν _C═O (amide, ketone)), 1728 (ν _C═O (carboxylic acid)), 3427 (ν _NH )
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 418, 513, 548, 588, 647 nm)
FAB-MS spectrum (m / z): 1112 ([M + H] ⁺ ).

¹ H-NMR spectrum (CD ₂ Cl ₂ ; δ (ppm)): δ = −2.6 (s, 2H, inner H), 0.0-0.3 (m, 36H, pivaloylamino), 2.3 (m, 2H, —C H ₂ COOH), 2.9-3.1 (m, 2H, -C H ₂ CH ₂ COOH), 7.2-7.4 (m, 8H, phenyl, amide), 7.8-8.0 (m, 8H, phenyl), 8.6-8.8 (m , 6H, pyrrole-β), 8.8 (m, 4H, phenyl), 9.1 (s, 1H, pyrrole-β).

<Example 7>
In Example 3, instead of 2- (4-carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin, 2- (3-Carboxypropanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin obtained in Example 6 was converted to glycyl-L-histidine methyl ester. Instead of L-alanyl-glycyl-L- (1-methyl) histidine methyl ester, 2- (3-((o-methyl) (1-methyl) histidylglycylalanyl) carbonylpropanoyl ) -5,10,15,20-tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin was synthesized.

  Obtained 2- (3-((o-methyl) (1-methyl) histidylglycylalanyl) carbonylpropanoyl) -5,10,15,20-tetrakis (α, α, α, α-o The analysis results of-(pivaloylamino) phenyl) porphyrin were as follows.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.24 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1679 (ν _{C = O} (amide, ketone)), 1728 (ν _{C = O} (ester)), 3426 (ν _NH )
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 418, 513, 548, 588, 646 nm)
FAB-MS spectrum (m / z): 1405 ([M + H] ⁺ ).

¹ H-NMR spectrum (CD ₂ Cl ₂ ; δ (ppm)): δ = −2.6 (s, 2H, inner H), 0.0-0.3 (m, 36H, pivaloylamino), 1.5 (m, 3H, —CH ( C H ₃ )-), 2.3 (m, 2H, -CH ₂ C H ₂ CONH-), 3.3-3.5 (m, 4H, -CH ₂ -Im, -C H ₂ CH ₂ CONH-), 3.6 (3H , s, -OCH ₃ ), 3.7 (3H, s, -N (CH ₃ )-), 4.2 (m, 2H, -COC H ₂ NH-), 4.7 (m, 2H, -COC H NH-), 6.9 (s, 1H, Im), 7.2-7.4 (m, 8H, phenyl, amide), 7.8-8.0 (m, 9H, Im, phenyl), 8.6-8.8 (m, 6H, pyrrole-β), 8.8 ( m, 4H, phenyl), 9.1 (s, 1H, pyrrole-β).

<Example 8>
In Example 4, 2- (4-((O-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexyl) Instead of sanoylamino) phenyl) porphyrin, 2- (3-((O-methyl) (1-methyl) histidylglycylalanyl) carbonylpropanoyl) -5,10,15,20-tetrakis (α , Α, α, α-o- (pivaloylamino) phenyl) porphyrin, 2- (3-((O-methyl) (1-methyl) histidylglycylalanyl) carbonylpropanoyl) -5,10 , 15,20-tetrakis (α, α, α, α-o- (pivaloylamino) phenyl) porphyrin iron (III) bromide was synthesized.

  Obtained 2- (3-((o-methyl) (1-methyl) histidylglycylalanyl) carbonylpropanoyl) -5,10,15,20-tetrakis (α, α, α, α-o The analysis results of-(pivaloylamino) phenyl) porphyrin iron (III) bromide were as follows.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.22 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1689 (ν _{C = O} (amide, ketone)), 1741 (ν _{C = O} (ester))
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 339, 419, 578 nm)
FAB-MS spectrum (m / z): 1457 ([M-Br] ⁺ ).

<Example 9>
In Example 3, N- (5- (2-methylimidazolyl-1-yl) pentyl) synthesized according to H. Nishide et al., Maclomolecules, 20, 1913 (1986) instead of glycyl-L-histidine methyl ester Using an amine, 2- (N- (5- (2-methylimidazolyl-1-yl) pentyl) amino) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α- o- (1-Methylcyclohexanoylamino) phenyl) porphyrin was synthesized.

  The resulting 2-((N- (5- (2-methylimidazolyl-1-yl) pentyl) amino) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o The analysis results of-(1-methylcyclohexanoylamino) phenyl) porphyrin were as follows.

Thin layer chromatography (chloroform / methanol: 10/1 (volume / volume): Rf: 0.6 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1679 (ν _{C = O} (amide, ketone)), 3426 (ν _NH )
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 427, 520, 556, 595, 653 nm)
FAB-MS spectrum (m / z): 1435 ([M + H] ⁺ ).

¹ H-NMR spectrum (CD ₂ Cl ₂ ; δ (ppm)): -2.6 (s, 2H, inner H), 0.1-1.0 (m, 52H, 1-methylcyclohexaneamide), 1.3 (m, 2H,- NH (CH ₂ ) ₂ C H _2- ), 1.5-1.7 (m, 4H, -NHCH ₂ C H ₂ CH ₂ C H _2- ), 1.8-2.0 (m, 2H, -C H ₂ CH ₂ CONH- ), 2.5 (s, 3H, Im (CH ₃ )), 2.6-2.8 (m, 4H, -COC H ₂ CH ₂ C H ₂ CO-), 3.0 (m, 2H, -NHCH ₂ ), 4.0 (m , 2H, -CH ₂ Im), 6.7-6.9 (m, 2H, Im), 7.3-7.6 (m, 5H, amide and phenyl), 7.7-8.0 (m, 8H, phenyl), 8.1 (s, 1H, Amide), 8.3-8.4 (m, 3H, phenyl), 8.6 (d, 1H, phenyl), 8.7-8.9 (m, 7H, pyrrole-β).

<Example 10>
2- (4- (1-((2-Methyl) imidazolyl-1-yl) pentylamino) carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α obtained in Example 9 -O- (1-methylcyclohexanoylamino) phenyl) porphyrin is reacted with cobalt chloride in dry tetrahydrofuran containing 2,6-lutidine to give a cobalt complex 2- (4- (1-((2- Methyl) imidazolyl-1-yl) pentylamino) carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin cobalt ( II) was synthesized quantitatively.

  The resulting 2- (4- (1-((2-methyl) imidazolyl-1-yl) pentylamino) carboxybutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o The analysis results of-(1-methylcyclohexanoylamino) phenyl) porphyrin cobalt (II) were as follows.

Thin layer chromatography (chloroform / methanol: 10/1 (volume / volume): Rf: 0.55 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1688 (ν _{C = O} (amide, ketone))
UV-visible absorption spectrum (CHCl ₃ ; λ _max : 407, 524, 559 nm)
FAB-MS spectrum (m / z): 1491 ([M] ⁺ ).

<Example 11>
In Example 3, in the same manner as in Examples 3 and 4, except that L-phenylalanyl-L-histidine methyl ester was used instead of glycyl-L-histidine methyl ester, 2- (4-(( O-methyl) histidylphenylalanyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin iron ( III) The bromide was obtained.

  2- (4-((O-methyl) phenylalanylhistidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1- The analysis results of methylcyclohexanoylamino) phenyl) porphyrin iron (III) bromide were as follows.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.31 (monospot))
Infrared absorption spectrum (cm ⁻¹ ): 1692 (ν _{c = o} (amide, ketone)), 1741 (ν _{c = o} (ester))
UV-visible absorption spectrum (CHCl ₃ , λ _max : 349, 423, 585 nm)
FAB-MS spectrum (m / z): 1637 ([M-Br] ⁺ ).

<Example 12>
In Example 3, except that glycyl-L- (3-methyl) histidine methyl ester was used instead of glycyl-L-histidine methyl ester, 2- (4- ( (O-methyl) (3-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl ) Porphyrin iron (III) bromide was obtained.

  The obtained 2- (4-((O-methyl) (3-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- ( The analysis results of 1-methylcyclohexanoylamino) phenyl) porphyrin iron (III) bromide were as follows.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.31 (monospot))
Infrared absorption spectrum (cm ⁻¹ ): 1690 (ν _{c = o} (amide, ketone)), 1740 (ν _{c = o} (ester))
UV-visible absorption spectrum (CHCl ₃ , λ _max : 346, 421, 581 nm)
FAB-MS spectrum (m / z): 1561 ([M-Br] ⁺ ).

<Example 13>
In Example 1, instead of 5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoylamino) phenyl) porphyrin copper (II), 5,10,15, 20-tetrakis (α, α, α, α-o- (1-adamantanoylamino) phenyl) porphyrin copper (II) was used, and instead of glycyl-L-histidine methyl ester in Example 3, L-Leucyl- 2- (4-((O-methyl) histidylleucyl) carbonylbutanoyl) -5,10,15,20- in the same manner as in Examples 1 to 4 except that L-histidine methyl ester was used. Tetrakis (α, α, α, α-o- (adamantanoylamino) phenyl) porphyrin iron (II) bromide was obtained.

  Obtained 2- (4-((O-methyl) histidylleucyl) carbonylptanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (adamantanoylamino) Analysis results of phenyl) porphyrin iron (III) bromide were as follows.

Thin layer chromatography (chloroform / methanol: 8/1 (volume / volume): Rf: 0.51 (monospot))
Infrared absorption spectrum (cm ^-1 ): 1692 (ν _{c = o} (amide, ketone)), 1739 (ν _{c = o} (ester))
UV-visible absorption spectrum (CHCl ₃ , λ _max = 345, 420, 579 nm)
FAB-MS spectrum (m / z) = 1755 ([M-Br] ⁺ ).

<Application example 1>
2- (4-((O-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methyl) synthesized in Example 4 Cyclohexanoylamino) phenyl) porphyrin Iron (III) bromide 0.1 μmol was made into 10 mL anhydrous toluene solution, and after nitrogen substitution, the mixture was stirred and mixed with dithionite aqueous solution in a heterogeneous system for about 2 hours to iron (II). Reduced. Under a nitrogen atmosphere, only the toluene layer was extracted, dehydrated and dried over anhydrous sodium sulfate, filtered, and the resulting toluene solution was transferred to a measurement cell and sealed. Thus, 2- (4-((o-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methylcyclohexanoyl) A toluene solution of amino) phenyl) porphyrin iron (II) complex was obtained.

The visible absorption spectrum of this solution was λ _max of 440 nm, 520 nm, and 544 nm, and the complex corresponded to a 5-coordinate deoxy form in which one histidine coordinated. When oxygen gas was blown into this solution, the spectrum immediately changed and spectra of λ _max = 429 nm and 551 nm were obtained. From this, it was found that the complex was an oxygenated complex. When nitrogen gas was blown into this oxygenated complex solution for 1 minute, the visible absorption spectrum reversibly changed from the oxygenated spectrum to the deoxy spectrum, and it was confirmed that the adsorption / desorption of oxygen occurred reversibly. Furthermore, when the operation of blowing oxygen and then nitrogen was repeated, it was revealed that oxygen adsorption / desorption can be continuously performed.

<Application example 2>
2- (4-((o-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o- (1-methyl) synthesized in Example 4 Cyclohexanoylamino) phenyl) porphyrin iron (III) bromide (20 μM) was included in human serum albumin (2.5 μM) according to the method described in JP-A-8-201873, and the prepared albumin-heme complex (porphyrin / 3 mL of an aqueous phosphate buffer solution (pH 7.4; 1/30 mM) of albumin (8 (mol / mol)) was transferred to a quartz spectroscopic measurement cell and sealed in a nitrogen atmosphere. The visible absorption spectrum is λ _max of 445 nm, 541 nm, and 568 nm, and the inclusion porphyrin iron (II) complex forms a Fe (II) high-spin five-coordinate complex with one intramolecular axial base coordinated. It was confirmed that

When oxygen was bubbled through this dispersion, λ _{max in the} visible absorption spectrum shifted to 432 nm and 553 nm, indicating the formation of an oxygenated complex. When nitrogen gas was blown into this oxygenated complex solution for 1 minute, the visible absorption spectrum reversibly changed from the oxygenated spectrum to the deoxytype spectrum, indicating that oxygen adsorption / desorption occurs reversibly. It was. In addition, when the operation of blowing oxygen and then nitrogen was repeated, it was revealed that oxygen adsorption / desorption can be continuously performed. The oxygen affinity (P ₅₀ value) was 2 Torr (37 ° C., pH 7.4). The half-life of the oxygen complex was 12 to 14 hours at 37 ° C. in air.

<Application example 3>
2- (4-((O-methyl) (3-methyl) histidylglycyl) carbonylbutanoyl) -5,10,15,20-tetrakis (α, α, α, α-o synthesized in Example 12 -(1-methylcyclohexanoylamino) phenyl) porphyrin iron (III) bromide (20 μm) was encapsulated in human serum albumin (2.5 μM) according to the method described in Japanese Patent Application No. 07-106314, 3 mL of a phosphate buffer aqueous solution (pH 7.4, 1/30 mM) of the heme complex (porphyrin / albumin: 8 (mol / mol)) was transferred to a quartz spectroscopic measurement cell and sealed in a nitrogen atmosphere. The visible absorption spectrum is λ _max of 444 nm, 540 nm, and 568 nm, and the inclusion porphyrin iron (II) complex forms a Fe (II) high-spin five-coordinate complex in which one intramolecular axial base is coordinated. It was confirmed that

When oxygen was bubbled through this dispersion, λ _{max in the} visible absorption spectrum shifted to 435 nm and 550 nm, indicating the formation of an oxygenated complex. When nitrogen gas was blown into this oxygenated complex solution for 1 minute, the visible absorption spectrum reversibly changed from the oxygenated spectrum to the deoxy-type vector, indicating that the adsorption and desorption of oxygen occurred reversibly. . In addition, when the operation of blowing oxygen and then nitrogen was repeated, it was revealed that oxygen adsorption / desorption can be continuously performed. The oxygen affinity (P ₅₀ value) was 1.8 Torr (37 ° C., pH 7.4). The half-life of the oxygen complex was 12 to 14 hours at 37 ° C. in air.

Claims (12)

  A porphyrin compound having an acyl group at the 2-position. Formula [I]:

(Here, R ₁ is a linear or alicyclic hydrocarbon group which may have a substituent, R ₂ is an alkylene group, R ₃ is an α-amino acid, or two α-amino acids. Dipeptide, R ₄ is a hydroxyl group, an alkyloxy group, a t-butyloxy group or a benzyloxy group, R ₅ is a hydrogen atom or a methyl group, and M is bonded to two pyrrole nitrogens out of four pyrrole nitrogens in the porphyrin ring. 2 hydrogen atoms or transition metal ions in the 4th to 5th periods, X ⁻ represents a halide ion, and n represents the number of X ⁻ represents the number obtained by subtracting 2 from the valence of the metal ion M) Porphyrin compounds shown. Formula [II]:

(Here, R ₆ is a linear or alicyclic hydrocarbon group which may have a substituent, R ₇ is an alkylene group, R ₈ is an α-amino acid or two α-amino acids. Dipeptide, R ₉ is a hydroxyl group, an alkyloxy group, a t-butyloxy group or a benzyloxy group, M is two hydrogen atoms bonded to two pyrrole nitrogens among the four pyrrole nitrogens in the porphyrin ring, or 5-period transition metal ion, X ⁻ represents a halide ion, and n represents the number of X ⁻ represents a number obtained by subtracting 2 from the valence of the metal ion. General formula [III]:

(Where R ₁₀ is a linear or alicyclic hydrocarbon group which may have a substituent, R ₁₁ is an alkylene group, R ₁₂ is an alkyleneamino group or alkyleneoxy group, and R ₁₃ is a hydrogen atom. M is a methyl group or an alkylene group, M is two hydrogen atoms bonded to two pyrrole nitrogens among the four pyrrole nitrogens in the porphyrin ring, or a transition metal ion in the 4th to 5th periods, and X ⁻ is a halide ion. And n representing the number of X ⁻ represents a number obtained by subtracting 2 from the valence of the metal ion).   The porphyrin compound according to any one of claims 1 to 4, wherein M is Fe or Co.   The porphyrin compound according to claim 5, wherein the valence of Fe is +2 or +3.   The porphyrin compound according to claim 5, wherein Co has a valence of +2.   An albumin-porphyrin complex formed by inclusion of the porphyrin compound according to any one of claims 1 to 7 in albumin.   The albumin-porphyrin complex according to claim 8, wherein the albumin is human serum albumin, bovine serum albumin, recombinant human serum albumin, or albumin multimer.   A surface-modified albumin-porphyrin complex in which a poly (ethylene glycol) chain is covalently bonded to the albumin-porphyrin complex according to claim 8 or 9 so that the average number of binding molecules per albumin molecule is 1-15. body.   The surface-modified albumin-porphyrin complex according to claim 10, wherein the poly (ethylene glycol) has a number average molecular weight of 1,000 to 20,000.   An artificial oxygen carrier containing the albumin-porphyrin complex according to any one of claims 8 to 11.