JP3405741B2 - Porphyrin metal complexes with proximal bases - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a porphyrin metal complex having an oxygen carrying function.

[0002]

2. Description of the Related Art Iron (II) porphyrin complexes present in hemoglobin and myoglobin reversibly adsorb and desorb oxygen molecules. Many studies have been reported in the past for the purpose of realizing a compound having an oxygen adsorption / desorption function similar to that of a natural porphyrin (II) complex with a synthetic complex. As an example, J. P. Collman, Acc
outs of Chemical Research
h, 10, 265 (1977); Basolo,
B. M. Hoffman and J.M. A. Ibera, i
bid, 8, 384 (1975). In particular, iron (II) 5,1 is a porphyrin iron (II) complex that is reported to be capable of forming a stable oxygen complex under room temperature conditions.
0,15,20-Tetra (α, α, α, α-o-pivalamidophenyl) porphyrin complex (JP Coleman et al., Journal of the American Chemical Society, vol. 97, p. 1427, 1975) There is.

[0003]

However, since these porphyrin complexes have bulky substituents on only one side of the porphyrin ring, the oxygen coordination complex forms a μ-dioxo dimer. However, it is oxidized into an iron (III) porphyrin complex that does not have oxygen-binding ability. Therefore, there is a strong demand for the development of iron (II) porphyrin complexes that give stable oxygen complexes at room temperature.

The present inventors believe that by introducing bulky substituents on both sides of the porphyrin ring, their oxidative deterioration behavior can be prevented and a more stable oxygen carrier can be provided, and the bulkiness is already high on both sides. A porphyrin metal complex having a substituent was synthesized and its reversible oxygen-binding ability was clarified (JP-A-3-128389). Further, it has been found that by embedding these iron (II) porphyrin complexes in a lipid bilayer, oxygen can be reversibly adsorbed and desorbed in an aqueous solution system (Japanese Patent Laid-Open No. 3-275687).
issue).

In the inventions proposed in JP-A-3-128389 and JP-A-3-275687, the intermolecular complex formation between the iron (II) porphyrin complex and the imidazole derivative (axial ligand) is balanced. Since it is a reaction, in order to obtain a complex having oxygen adsorption / desorption activity, it is necessary to make the imidazole derivative, which is an axial ligand, coexist excessively with the iron (II) porphyrin complex. However, it is needless to say that the amount of the imidazole derivative used should be as small as possible when it is intended to be applied to a living body.

[0006]

Means for Solving the Problems The inventors of the present invention have made extensive studies on the molecular design and function expression of a metalloporphyrin complex capable of forming a more stable oxygen complex. As a result, bulky substituents were introduced on both sides of the porphyrin ring, and the imidazole derivative, which is a basic axial ligand necessary for effectively exhibiting the oxygen adsorption / desorption ability, was added to 1 mol of porphyrin per mole. In other words, the porphyrin with a novel structure having a proximal base can be bound to the molecule at a ratio of 1 to prevent the oxidative deterioration behavior and provide a more stable oxygen carrier. I found it. The present invention has been completed based on the above findings.

The present invention will be summarized as follows.

[Chemical 3] (Here, k is an integer of 0 to ₁ , R ₁ is an alkylene group, R
₂ represents a group that does not hinder the coordination of the imidazolyl group to the central transition metal ion M when the following transition metal ions M of the fourth to fifth periods are coordinated. ) Porphyrin,
Alternatively, the following general formula [II] in which a transition metal ion of the 4th to 5th periods is coordinated to the porphyrin

[Chemical 4] [Here, k is an integer of 0 to ₁ , R ₁ is an alkylene group, R
₂ is a group that does not hinder the coordination of the imidazolyl group to the central transition metal, M is a transition metal ion of the 4th to 5th periods, X ⁻ is a halogen ion (chlorine ion, bromine ion), X ⁻
The number n of n represents an integer obtained by subtracting 2 from the valence of the transition metal ion. ] It is related with the porphyrin metal complex shown by these.

In the above general formulas [I] to [II], R ₁
Is a C ₃ -C ₁₀ alkylene group, preferably a tetramethylene group. R ₂ is a group that does not hinder the coordination of the imidazole to which they are bound to the central transition metal, and is preferably hydrogen, a methyl group, an ethyl group or a propyl group. As the transition metal ion M, iron and cobalt ions are particularly preferable.

In the present invention, a complex capable of specifically binding oxygen is a complex in which the central transition metal is in a +2 valent state and one proximal base is coordinated.
The following general formula [III]

[Chemical 5] There is something shown in.

The porphyrin or porphyrin metal complex represented by the above general formulas [I] to [II] can be synthesized, for example, by the following process.

First, 2,6-dimethoxybenzaldehyde and pyrrole (equimolar) are condensed in a suitable solvent,
5,10,15,20-Tetra (2 ′, 6′-dimethoxyphenyl) porphyrin is synthesized. Fatty acids such as acetic acid, propionic acid and butyric acid are used as the solvent. The reaction temperature can be adjusted depending on the type of solvent and other conditions, but is usually selected between 80 and 120 ° C. The reaction time is 5 to 12 hours, preferably 6 to 8 hours. After condensation in this way, the tar-like reaction mixture obtained by filtering the reaction solvent is purified by, for example, silica gel column chromatography, and the desired product 5,10,15,20-tetra (2 ', 6'- Dimethoxyphenyl) porphyrin is obtained. Then, the 5,10,15,20-tetra (2 ′, 6′-dimethoxyphenyl) porphyrin was dissolved in a suitable dry solvent (dichloromethane, chloroform, tetrahydrofuran, etc.) to give 40 times or more molar amount of boron tribromide. Is added under ice cooling, and the mixture is stirred at room temperature for 10 to 24 hours. The reaction solution was added dropwise to ice water and extracted with an organic solvent such as ethyl acetate, and then the organic layer was evaporated to dryness and purified by silica gel column chromatography.
20-Tetra (2 ', 6'-dimethoxyphenyl) porphyrin is obtained.

A dry tetrahydrofuran solution containing the 5,10,15,20-tetra (2 ', 6'-dimethoxyphenyl) porphyrin was added to the following general formula [IV]:
Add the acid chloride or acid bromide of K + 2, K + 2-dimethylalkanoic acid (7 times cell). General formula (IV)

[Chemical 6]

Then, a small amount of 4-dimethylaminopyridine is added and the reaction is continued for 10 to 24 hours. The reaction mixture is extracted with an appropriate organic solvent (dichloromethane, chloroform, ether, etc.), washed with dilute hydrochloric acid and then with water. The residue obtained by thickening the organic layer and evaporating the solvent under reduced pressure is purified by, for example, silica gel column chromatography to obtain the desired product represented by the following general formula [V]. General formula [V]

[Chemical 7]

A solution of the compound represented by the above general formula [V], for example, a dry acetonitrile solution, is subjected to N-- under an argon atmosphere.
It is added to the acid chloride or acid bromide of imidazolylalkanoic acid (10 to 40 times by mole) and allowed to react at 30 to 70 ° C. for 6 to 24 hours, preferably 8 to 12 hours. The reaction mixture is extracted with an appropriate organic solvent (dichloromethane, chloroform, ether, etc.), washed with dilute hydrochloric acid and then with water. The residue obtained by collecting the organic layers and distilling the solvent off under reduced pressure is purified by, for example, silica gel column chromatography to obtain the desired product of the general formula [I].

Next, the porphyrin metal complex represented by the general formula [II] is obtained as follows. That is, the central transition metal M is introduced into the porphyrin of the general formula [I] obtained as described above by a conventional method (for example, edited by David Drophin, The Porphyrins, 1978, Academic Press Co., Ltd.). As a result, the porphyrin metal complex represented by the general formula [II] is obtained. Generally, in the case of an iron complex, a porphinato iron (III) complex is obtained, and in the case of a cobalt complex, a porphinato cobalt (II) complex is obtained.

Further, the complex represented by the general formula [III] is
It is obtained as follows. That is, among the complexes represented by the general formula [II] obtained as described above, in the case of an iron complex, an iron (III) complex is formed at the end of the synthesis, and therefore, a suitable reducing agent (sodium dithionite) is used. , Ascorbic acid, etc.) to reduce the central iron from trivalent to divalent by a conventional method to obtain a complex represented by the general formula [III]. In the case of a cobalt complex, the general formula [II
I] form a complex.

In the present invention, the complex represented by the general formula [III] is oxygen-containing by embedding in a liposome bilayer membrane composed of a lipid in an organic solvent (toluene, benzene, tetrahydrofuran, etc.) or in neutral water. Contact with produces a stable oxygen complex. Further, these complexes adsorb and desorb oxygen according to the oxygen partial pressure. This oxygen adsorption / desorption can be repeatedly carried out reversibly, and therefore the above-mentioned general formula [II
The complex represented by I] can be used as an oxygen adsorption / desorption agent or an oxygen carrier.

[0018]

EXAMPLES AND REFERENCE EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples.

<Reference Example 1> (A). 1500 ml of propionic acid containing 20 g of 2,6-dimethoxbenzaldehyde was heated and stirred at 100 ° C., 8.05 g of pyrrole was added, and the mixture was heated and stirred as it was for 7 hours. After returning to room temperature, it was left as it was overnight. The reaction solution was filtered with a glass filter, and the collected product was washed with cold methanol, and then 5,10,15,20-tetra (2 ', 6'-dimethoxyphenyl) porphyrin was purified using a silica gel column (dichloromethane). Released. Yield about 3.8 g (yield about 15%). Thin layer chromatography (Merck silica gel plate, dichloromethane): Rf
= 0.60 (mono spot). Infrared absorption spectrum (N
aCl, cm ^-1 ): 1580 (υc = c (phenyl nucleus)), 1280 (υc-o-c (methoxy)). Visible absorption spectrum (CH ₂ Cl ₂ , λmax 642, 5
88, 544, 512, 420 nm). ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , TMS standard, δ (pp
m)) 8.8 (8H, s, pyrrole), 3.5
_{(24H, s, OCH 3)} -2.8 (2H, s, inn
er).

(B). 5,10,15,20-tetra (2 ', 6'-dimethoxyphenyl) porphyrin 3.
50 ml of a dichloromethane solution containing 0 g was stirred under ice cooling, 35.2 g of boron tribromide was added thereto, and the mixture was stirred under ice cooling for about 2 hours and then at room temperature for about 20 hours. The reaction solution was added dropwise to ice water, extracted with 250 ml of ethyl acetate, washed with a 5% aqueous sodium hydrogen carbonate solution, and then washed with water. The chloroform layer was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. This was fractionated and purified by a silica gel column (ethyl acetate / methanol (20/1) (volume / volume)), and the target substance that flowed out was collected and evaporated to dryness. Yield about 2.
4 g (yield about 92%). Infrared absorption spectrum (NaC
l, cm ^-1 ): 3350 (υOH), 1580 (υc = c)
(Phenyl nucleus)). Visible absorption spectrum (CH ₃ OH,
λmax 643,585,546,512,415n
m. ¹ H-nuclear magnetic resonance spectrum (CD ₃ OD, TMS standard, δ (ppm)) 8.8 (8 H, s, pyrrol)
e), -2.8 (2H, s, inner).

<Example 1> (1). Acid chloride of 3,3-dimethylbutanoic acid 2.8
250 ml of dry tetrahydrofuran in which ml (0.02 mol) was dissolved was synthesized in Reference Example 1 (B)
5.0 g (6.7 mmol) of 0,15,20-tetra (2 ′, 6′-dihydroxyphenyl) porphyrin
And 4-dimethylaminopyridine 6.6 g (53 mmo
1 l of a dry tetrahydrofuran solution containing 1) was added dropwise under an argon atmosphere over about 1 hour. The reaction was allowed to proceed at room temperature for about 12 hours. The residue obtained by evaporation was dissolved in 500 ml of chloroform and washed with water. This was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. This was fractionated and purified with a silica gel column (chloroform / diethyl ether (10/1) (volume / volume)), and the target substances of the fractionation were collected and dried in vacuo. Thus
5,10,15-tri (2 ', 6'-di (3 ", 3"-
Dimethylbutanoyloxy) phenyl) -20- (2 '
-Hydroxy-6 '-(3 ", 3" -dimethylbutanoyloxy) phenyl) porphyrin as a purple solid, yield 0.96 mg (0.67 mmol) (yield 10
%). Elemental analysis value (% by weight): C72.1
(72.3), H6.91 (6.92), N3.82
(3.92) (However, the values in parentheses are C ₈₆ H ₉₈ N ₂ O ₁₅
Shows the calculated value for). FAB-mass spectrum: 1
428 [M] ⁺ . Infrared absorption spectrum (NaCl, cm
-1): 1760 (υc = o (ester)), 3480
(ΥOH (alcohol)). Thin layer chromatography (Merck silica gel plate, chloroform / diethyl ether (10/1) (volume / volume)): Rf: 0.57
(Mono spot). Visible absorption spectrum (CHCl ₃ ,
λmax 653,582,534,507,413n
m). ¹ H-nuclear magnetic resonance spectrum (CHCl ₃ , TM
S standard), δ (ppm)) 8.9 (8H, s, pyrr)
ole), 7.5-7.9 (12H, m, phenyl)
-H), 1.1 to 1.4 (14H, m, -CH2-),
_{-0.6~0.1 (63H, m, -CH 3} ), - 3.0
(2H, d, inner).

(2). 7.5 g (45 mmol) of hydrogen chloride salt of 5- (N-imidazolyl) valeric acid was mixed with 300 ml of dry acetonitrile, and under argon atmosphere, 15.3 ml (0.19 mol) of oxalyl chloride was added,
It was heated at 60 to 70 ° C. for about 1 hour as it was. To the residual solid obtained by evaporation, 5,10,1 synthesized in Example 1 (1)
5-tri (2 ', 6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-hydroxy-6'-(3 ", 3" -dimethylbutanoyloxy)
Phenyl) porphyrin 1.5 g (1.0 mmol)
And 200 ml of dry acetonitrile containing 9 ml (63 mmol) of triethylamine under an argon atmosphere to about 1
It dripped over time. After the dropping is completed, about 6 at 60 to 70 ° C
The mixture was heated and stirred for an hour. The residual solid obtained by evaporation was dissolved in 500 ml of chloroform and washed with water. This was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. This was fractionated and purified by a silica gel column (chloroform / methanol (20/1) (volume / volume)), and the target substances of the fractionation were collected and vacuum dried. Thus, 5,1
0,15-tri (2 ', 6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-5 "
-(N-imidazolyl) valeroylroxy-6'-
(3 ", 3" -dimethylbutanoyloxy) phenyl)
The porphyrin is 0.9 g (0.5
7 mmol) (yield 54%). Elemental analysis value (% by weight): C72.3 (71.5), H7.15
(7.02), N5.24 (5.32) ( where values in parentheses indicate calculated values for _{C 94 H 110 N 6 O 16} ). F
AB-mass spectrum: 1578 [M-2] ⁺ . Infrared absorption spectrum (NaCl, cm-1): 1761 (υc
= O (ester)). Thin layer chromatography (Merck silica gel plate, chloroform / diethyl ether (20/1) (volume / volume)): Rf = 0.24 (monospot). Visible absorption spectrum (CHCl ₃ , λm
ax 654, 583, 536, 507, 414 nm).
¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , TMS standard), δ (ppm)) 8.8 (8 H, d, pyrrol)
e), 7.4 to 7.8 (12H, m, phenyl-
H), 6.1 to 6.8 (3H, m, imidazol
e) 0.7~2.8 (22H, m, -CH 2 -), -
_{0.5~0.4 (63H, m, -CH 3} ), - 3.0
(2H, s, inner).

<Example 2> 5,10,15-tri (2 ', 6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (synthesized in Example 1 (2) 2'-5 "-(N-imidazolyl) valeroylroxy-6 '-(3", 3 "-dimethylbutanoyloxy) phenyl) porphyrin 1.0
g (63 mmol) of dry tetrahydrofuran 200 m
It was dissolved in ol and replaced with nitrogen. Ferrous bromide (FeBr ₂ nH ₂ O) (5.37 g) and 2,6-lutidine (2.2 ml, 19 mmol) were added thereto, and the mixture was refluxed under heating. After heating for 6 hours, the solvent was evaporated to dryness under reduced pressure, the remaining solid was dissolved in 500 ml of chloroform, washed with diluted hydrochloric acid water,
Washed with water. The chloroform layer was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. This is a silica gel column (chloroform / methanol (20/1)
(Volume / volume)), fractionation and purification were performed, and the target substances of the fractionation were collected and vacuum dried. Thus, 5,10,15-tri (2 ', 6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-5 "-(N-imidazolyl) valeroylroxy-6'. -(3 ", 3" -dimethylbutanoyloxy) phenyl) porphyrinatoiron was obtained in a yield of 1.0 g (yield 62%). Elemental analysis value (% by weight): C66.2 (65.9), H6.43
(6.35), N4.81 (4.90) ( where values in parentheses indicate calculated values for _{C 94 H 108 N 6 O 16} FeBr). FAB-mass spectrum: 1713 [M-1] ⁺ . Infrared absorption spectrum (NaCl, cm-1): 1761
(Υc = o (ester)). Thin layer chromatography (Merck silica gel plate, chloroform / diethyl ether (20/1) (volume / volume)): Rf = 0.2
5 (mono spot). Visible absorption spectrum (toluene,
λmax 680, 648, 582, 511, 413n
m).

<Example 3> (1). According to the same procedure as in Example 1 (1), except that the acid chloride of 2,3-dimethylpropanoic acid was used instead of the acid chloride of 3,3-dimethylbutanoic acid.
5,10,15-tri (2 ', 6'-di (3 ", 3"-
Dimethylpropanoyloxy) phenyl) -20-
(2'-Hydroxy-6 '-(3 ", 3" -dimethylpropanoyloxy) phenyl) porphyrin was obtained as a purple solid in a yield of 0.92 g (10% yield).
Elemental analysis value (% by weight): C71.2 (71.4), H
6.48 (6.37), N4.06 (4.21 ) ( where values in parentheses indicate calculated values for _{C 79 H 84 N 2 O 15} ). FAB-mass spectrum: 1330 [M] ⁺ . Infrared absorption spectrum (NaCl, cm-1): 1760
(Υc = o (ester)), 3480 (υOH (alcohol)). Thin layer chromatography (Merck silica gel plate, chloroform / methanol (100/1) (volume / volume)): Rf = 0.18 (monospot). Visible absorption spectrum (CHCl3, λmax 654, 58
2,535,506,412 nm). 1H-nuclear magnetic resonance spectrum (CDCl3, TMS standard), δ (pp
m)) 8.7 (8H, d, pyrrole), 7.2-
7.8 (12H, m, phenyl-H), -0.7 ~
0.0 (63H, m, -CH3), -3.0 (2H,
s, inner).

(2). In Example 1 (2), 5, 10,
15-tri (2 ', 6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-hydroxy-6'-(3 ", 3" -dimethylbutanoyloxy) phenyl ) 5,10,1 instead of porphyrin
5-tri (2 ', 6'-di (2 ", 2" -dimethylpropanoyloxy) phenyl) -20- (2'-hydroxy-6'-(2 ", 2" -dimethylpropanoyloxy) phenyl ) 5,10,15-tri (2 ', 6'-di (2 ", 2" -dimethylpropayloxy) phenyl) was prepared according to the same procedure except that porphyrin was used.
1.2 g (70% yield) of -20- (2'-5 '-(N-imidazolyl) valeroylroxy-6'-(2 ", 2" -dimethylpropanoyloxy) phenyl) porphyrin as a purple solid. Obtained in. Elemental analysis rate (% by weight): C70.6 (70.5), H6.49 (6.5)
3), N5.58 (5.67) (However, the values in parentheses are
Calculated values for C ₈₇ H ₉₆ N ₆ O ₁₆ are shown). FAB-mass spectrum: 1481 [M-1] ⁺ . Infrared absorption spectrum (NaCl, cm-1): 1757 (υc = o (ester)). Thin layer chromatography (Merck silica gel plate, chloroform / methanol (20/1) (volume / volume)): Rf = 0.32 (monospot). Visible absorption spectrum (CHCl ₃ , λmax 654, 582,
535, 506, 412 nm. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , TMS standard), δm, phenyl
-H), 6.6 to 7.2 (3H, m, imidazol
e) 1.0~3.6 (8H, m, -CH 2 -), - 0.
_{6~10.1 (63H, m, -CH 3} ), - 3.0 (2
H, d, inner).

(3). In Experimental Example 2, 5, 10, 15-
Tri (2 ', 6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-5 "-(N-imidazolyl) valeroylroxy-6'-(3", 3 "-
Instead of dimethylbutanoyloxy) phenyl) porphyrin, 5,10,15-tri (2 ', 6'-di (2 ", 2" -dimethylpropanoyloxy) phenyl) -20- (2'-5 "- 5,10,15-tri (2 ′, 6′-di (according to the same procedure except that (N-imidazolyl) valeroylroxy-6 ′-(2 ″, 2 ″ -dimethylpropanoyloxy) phenyl) porphyrin was used. 2 ", 2" -dimethylpropanoyloxy) phenyl) -20- (2'-hydroxy-6 '-(2 ",
Iron 2 "-dimethylpropanoyloxy) phenyl) porphyrinato was obtained in a yield of 0.95 g (58% yield). Obtained by elemental analysis (wt%). Elemental analysis (wt%): C64. .8 (64.7), H5.50 (5.3)
6), N5.13 (5.20) (However, the values in parentheses are
Calculated values for C ₈₇ H ₉₄ N ₆ O ₁₆ FeBr are shown). F
AB-mass spectrum: 1536 [M-Br] ⁺ . Infrared absorption spectrum (NaCl, cm-1): 1757 (υc = o
(Ester)), 3315 (υOH (alcohol)). Thin layer chromatography (Merck silica gel plate, chloroform / acetone (50/1) (volume / volume)):
Rf = 0.2 (mono spot).

<Example 4> 5,10,15-tri (2 ', 6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'- synthesized in Example 2 5 "-(N-imidazolyl) valeroylroxy-6 '-(3", 3 "-dimethylbutanoyloxy) phenyl) porphyrin 1.0
g was dissolved in 50 ml of dry tetrahydrofuran, and the atmosphere was replaced with nitrogen. Cobalt chloride (CoCl ₂ ) 3.5
g and then 0.43 g of 2,6-lutidine were added and the mixture was refluxed with heating. After heating for 3 hours, the mixture was evaporated to dryness, the remaining solid was dissolved in 250 ml of chloroform and washed with water. The chloroform layer was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. This was fractionated and purified by a silica gel column (chloroform / methanol (20/1) (volume / volume)), and the target substances of the fractionation were collected and vacuum dried. In this way, 5,10,15-tri (2 ', 6'-di (3 ", 3"
-Dimethylbutanoyloxy) phenyl) -20-
(2'-5 "-N-imidazolyl) valeroylroxy-
The amount of 6 '-(3 ", 3" -dimethylbutanoyloxy) phenyl) porphinatocobalt was 0.98 g (yield 9
1%). Elemental analysis value (% by weight): C68.9 (6
9.0), H6.64 (6.65), N5.27 (5.
13) (however, the value in the parenthesis shows the calculated value for C ₉₄ H ₁₀₈ N ₆ O ₁₆ Co). FAB-mass spectrum: 16
37 [M] ⁺ . Infrared absorption spectrum (NaCl, cm-
1): 1757 (υc = o (ester)), 3315
(ΥOH (alcohol)). Thin layer chromatography (Merck silica gel plate, chloroform / methanol (20/1) (volume / volume)): Rf = 0.28 (monospot). Visible absorption spectrum (CHCl ₃ , λma
x553,522,403nm).

<Example 5> (1). In Example 1 (2), instead of the hydrogen chloride salt of 5- (N-imidazolyl) valeric acid, 5- (N- (2
-Methylimidazolyl)) 5,10,15-tri (2 ', 6'-di (2 ", 2" -dimethylpropanoyloxy) phenyl) following the same procedure but using the hydrogen chloride salt of valeric acid. -20- (2'-5 "-(N- (2
-Methylimidazolyl)) valeroylroxy-6'-
(2 ″, 2 ″ -dimethylpropanoyloxy) phenyl) porphyrin was obtained as a purple solid in a yield of 1.1 g (70% yield). Elemental analysis value (% by weight): C71.6
(71.6), H6.99 (7.08), N5.31
(5.27) (However, the values in parentheses are C ₉₅ H ₁₁₂ N ₆ O ₁₆
Calculated value for Co is shown). FAB-mass spectrum: 1594 [M] ⁺ . Infrared absorption spectrum (NaCl, c
m-1): 1757 (υc = o (ester)). Thin layer chromatography (Merck silica gel plate, chloroform / methanol (20/1) (volume / volume)): R
f = 0.32 (mono spot). Visible absorption spectrum (CHCl ₃ , λmax 654, 582, 535, 50
6,412 nm).

(2). In Example 2, 5, 10, 15-
Tri (2 ', 6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-5 "-N-imidazolyl) valeroylroxy-6'-(3", 3 "-dimethyl Instead of butanoyloxy) phenyl) porphyrin, 5,10,15-tri (2 ', 6'-di (2 ", 2" -dimethylpropanoyloxy) phenyl) -20- (2'-5 "- N- (2-methylimidazolyl)) valeroylroxy-6 '-(2 ", 2" -dimethylpropanoyloxy) phenyl) porphyrin was used in the same manner except that 5,10,15-tri (2', 6) was used. '-Di (2 ", 2" -dimethylpropanoyloxy) phenyl) -20- (2'-5 "-(N- (2
-Methylimidazolyl) valeroylroxy-6'-
(2 ", 2" -dimethylpropanoyloxy) phenyl) porphyrinato iron was obtained in an amount of 0.88 g (yield 58).
%). Elemental analysis rate (wt%): C66.2
(66.0), H6.35 (6.42), N4.82
(4.86) (However, the values in parentheses are C ₉₅ H ₁₁₀ N ₆ O ₁₆
Calculated values for FbBr are shown). FAB-mass spectrum: 1728 [M] ⁺ . Infrared absorption spectrum (NaCl,
cm ^-1 ): 1757 (υc = o (ester)), 331
5 (υOH (alcohol)). Thin layer chromatography (Merck silica gel plate, chloroform / acetone (50/1) (volume / volume)): Rf = 0.2 (monospot).

<Reference Example 2> 5,10,15-tri (2 ′, 6 ′) synthesized in Example 2
-Di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-5 "-N-imidazolyl) valeroylroxy-6 '-(3", 3 "-dimethylbutanoyloxy) phenyl) porphyrinato Iron 0.86mg
(0.5 μmol) was used as 10 ml of an anhydrous toluene solution, and after nitrogen substitution, the mixture was stirred with a dithionous acid aqueous solution in a heterogeneous system to reduce to iron (II). Under a nitrogen atmosphere, only the toluene layer was extracted, dehydrated and dried over anhydrous sodium sulfate, filtered, and the obtained toluene solution was transferred to a measurement cell and sealed.
Thus, iron (II) -5,10,15-tri (2 ',
6'-di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-5 "-(N-imidazolyl)
A toluene solution of a valeroylroxy-6 ′-(3 ″, 3 ″ -dimethylbutanoyloxy) phenyl) porphyrin) complex was obtained. The visible absorption spectrum of this solution is λm
It has ax 561, 535, 429 nm and shows that the imidazole site corresponds to the intramolecularly coordinated 5-coordinate deoxy form.

When oxygen gas was blown into this solution, the spectrum immediately changed and a spectrum of λmax 544 and 426 nm was obtained. This clearly indicates that it is an oxygenated complex. Nitrogen gas was added to this oxygenated complex solution in an amount of 1
It was confirmed that the visible absorption spectrum was reversibly changed from the oxygenation spectrum to the deoxy spectrum by blowing for a minute or by freezing and degassing the solution, and the adsorption and desorption of oxygen occurred reversibly. The operation of blowing oxygen and then blowing nitrogen was repeated, and oxygen adsorption / desorption could be continuously performed.

Reference Example 3 5,10,15-tri (2 ′, 6 ′) synthesized in Example 2
-Di (3 ", 3" -dimethylbutanoyloxy) phenyl) -20- (2'-5 "-(N-imidazolyl) valeroyloxy-6 '-(3", 3 "-dimethylbutanoyloxy) phenyl) Porfinato iron 0.86mg
A chloroform solution of (0.5 μmol) and dimyristoylphosphatidylcholine 68.7 mg (0.05 mmol) was dried to a thin film with a rotary evaporator. 20 ml of a 1/15 M phosphate buffer having a pH of 7.0 to 8.0 was added thereto, and ultrasonic irradiation (60 W, 10 W
Minutes). The solution was replaced with nitrogen, a small amount of ascorbic acid aqueous solution was added, and the solution was transferred to a measurement cell and sealed. Thus, iron (II) -5,10,15-tri (2 ', 6 "-di (3", 3 "-dimethylbutanoyloxy) phenyl)
A liposome solution of -20- (2'-5 "-(N-imidazolyl) valeroyloxy-6 '-(3", 3 "-dimethylbutanoyloxy) phenyl) porphyrin complex was obtained. Visible absorption of this solution The spectrum is λmax56
At 2,536,432 nm, it corresponds to the deoxy type.

When oxygen gas was blown into this solution, the spectrum immediately changed, and a spectrum of λmax 547,424 nm was obtained. This clearly indicates that it is an oxygenated complex. Nitrogen gas was added to this oxygenated complex solution in an amount of 1
It was confirmed that the visible absorption spectrum was reversibly changed from the oxygenation spectrum to the deoxy spectrum by blowing for a minute or by freezing and degassing the solution, and the adsorption and desorption of oxygen occurred reversibly. The operation of blowing oxygen and then blowing nitrogen was repeated, and oxygen adsorption / desorption could be continuously performed.

[0034]

The porphyrin-based porphyrin metal complex according to the present invention is obtained by introducing a bulky substituent group and a proximal base on both sides of a metalloporphyrin derivative known to have an oxygen binding function. It has an excellent oxygen carrying function.

Continuation of front page (56) Reference JP-A-3-275687 (JP, A) JP-A-3-128389 (JP, A) Journal of the Chemical Society of Japan, 1988, 1988 No. 10, 1713-1718 J. Am. Chem. Soc. , 1980, Vol. 102, No. 12, pp. 4182-4192 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 487/22 CAPLUS (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound represented by the general formula [I]: (Where, k is an integer of 0 to 1, R ₁ represents an alkylene group, R ₂ is hydrogen, methyl group, ethyl group or pro
Indicates a pill group . ) Or a general formula [II] in which a transition metal ion of the 4th to 5th periods is coordinated to the porphyrin. [Here, k is an integer of 0 to 1, R ₁ represents an alkylene group, R ₂ is hydrogen, methyl group, ethyl group or pro
Represents a pill group , M is a transition metal ion of the fourth to fifth period
Shows, X ^- represents chlorine ion or a bromine ion, X ^-
The number n indicates the integer obtained by subtracting 2 from the valence of the transition metal ion. ] The porphyrin metal complex shown by these. 2. The porphyrin or porphyrin metal complex according to claim 1, wherein R ₁ is a C ₃ -C ₇ alkylene group. 3. The porphyrin metal complex according to claim 1, wherein M is Fe or Co. 4. The porphyrin metal complex according to claim 4, wherein the valence of Fe is +2 or +3. 5. The porphyrin metal complex according to claim 4, wherein the valence of Co is +2.