JPH0249315B2 - SOSUISEICHIKANKIOJUSURUHORUFUIRINOYOBISONOSAKUTAI - Google Patents

Description

[Detailed description of the invention]

This invention relates to porphyrins having hydrophobic substituents and complexes thereof. Iron ()porphyrin complexes in hemoglobin and myoglobin reversibly adsorb and desorb oxygen molecules. In order to synthesize a complex with an oxygen adsorption/desorption function similar to such a natural porphyrin iron() complex,
Many studies have been published so far. Examples include J.P. Collman, Accounts of Chemical
Research 10 265 (1977); F. Basolo, B.M.
Hoffman and JAIbers, ibid., 8 384 (1975)
etc. In particular, iron()-5,10,15,20-tetra [α, α, α, α-(O-pyrin barazidophenyl)] porphyrin complex (JPCollman et al. Journal
of American Chemical Society 97 1427
(1975)). However, if even a small amount of water coexists with this complex, it will be immediately oxidized, making it impossible to generate an oxygen complex. For this reason, the development of iron()porphyrin complexes that provide oxygen complexes even in the coexistence of water at room temperature is being promoted. The applicant has obtained the above-mentioned iron()-5,10,15,20-tetra[α,α,α,α-(O-pivalamidophenyl)] under physiological conditions of water and room temperature.
In order for the porphyrin (hereinafter referred to as Fe()Tpiv PP) complex to provide a stable oxygen complex and act as an oxygen carrier, the complex may be embedded, for example, in the hydrophobic block B part of an ABA type block copolymer, or We have discovered that packaging phospholipids in a hydrophobic double-layer membrane inhibits oxidation by water or T ⁺ ₃ and allows the required functions to be exerted, and we have already filed applications (Japanese Patent Application Laid-Open No. 55-38812 and (No. 57-206613). The inventors developed the above idea and developed Tpiv
We believe that a more effective oxygen carrier can be provided by increasing the hydrophobicity of the porphyrin by replacing the pivaloyl group of PP with another more hydrophobic substituent, and have developed the present invention. I was able to complete it. The compounds of this invention have the general formula (Here, R is an alkyl group having 17 to 25 carbon atoms,
Porphyrin (meso-tetra [α, α, α, α-(O-substituted amidophenyl)] porphyrin having a hydrophobic substituent represented by a benzyl group or a cyclohexyl group) and a complex in which a central iron is coordinated to the porphyrin, i.e. ,formula Iron complexes represented by, as well as complexes in which the central iron is in a divalent state and one or two basic axial ligands are arranged, that is, the formula (Here, L is a basic axial ligand, x and y are 0
or 1, and x+y is a complex represented by 1 or 2). In order to produce the porphyrin represented by formula (A), known methods (see J.P. Collman et al., supra.
A specified acid chloride (R-COCl) ( Here, R is as defined above) is reacted at a ratio of 4 times the mole or more. The reaction temperature is usually 0°C to room temperature. By introducing a central iron into the thus obtained porphyrin of formula (A) by a conventional method, an iron complex represented by formula (B), namely 5,10,15,20-meso-tetra [α, α, α, α-(O-substituted amidophenyl)]
Iron porphynate is obtained. In order to obtain the complex represented by formula (C), the central iron of the iron complex represented by formula (B) is reduced by a conventional method in the presence of the axial ligand L using a suitable reducing agent. This basic axial ligand L has the formula (Here, R _a is a group that does not inhibit the coordination of the imidazole, preferably hydrogen, methyl group, ethyl group, and propyl group (including isomers), and R _b to R _d are hydrogen or any substituent such as an alkyl group. , trityl group, carboxylic acid ester group), or the formula (Here, R _e and R _i are the same groups as R _a , R _f ~ _{R h}
is a pyridine represented by R _b to R _d (similar groups). When the complex represented by formula (C) comes into contact with oxygen, it coordinates with one of the axial ligands L to form an oxygen complex. This desorbs oxygen under degassing. This oxygen adsorption/desorption can be repeated reversibly and acts as an oxygen adsorption/desorption agent and an oxygen carrier. Example 1 (A) Meso-tetra(O-aminophenyl)porphyrin (mixture of 4 isomers) was synthesized by a known method and subjected to silica gel column (acetone/
ether = 1/1 volume) using α, α, α,
The α-isomer was eluted and isolated. (B) About 300 ml of an acetone ether (1/1) solution containing about 0.3 gr of meso-tetra[α,α,α,α-(O-aminophenyl)]porphyrin was stirred under ice cooling. To this was added 2 ml of dry pyridine and then 2.5 ml of stearoyl chloride, and the mixture was stirred for 1 hour under ice-cooling and then for 2 hours at room temperature. The residue obtained by evaporation was dissolved in 200 ml of CHCl ₃ and washed with dilute aqueous ammonia, then with water, treated with gelite, and washed with water. This was dehydrated with Na ₂ SO ₄ and then filtered, and the filtrate was evaporated to dryness at a bath temperature of 30° C. or less. This was fractionated and purified using a silica gel column, and the desired portion of the benzene/ether (7/3) (volume/volume) flow was collected and evaporated to dryness. Purification using a silica gel column was performed again. Yield approximately 0.56gr (yield approximately 90%). This was further purified using a silica gel column (BioBeads SX-8,
benzene). Electric field desorption mass spectrum measurement: M
+1 ₍ 1403) ( _molecular weight _{of C92H122N8O4} 1402). Elemental analysis value (weight%): C78.66 (78.7), H8.52
(8.7), N7.60 (8.0) However, the values in parentheses are
Calculated values for C ₉₂ H ₁₂₂ N ₈ O ₄ are shown. 13C-Nuclear magnetic resonance spectrum (solvent CDCl ₃ , TMS standard)
δ (ppm): 170.5(1), 147.0(2), 138.0(3), 134.8
(4), 131.6(5), 129.8(6), 122.8(7), 121.1(8),
115.0(9), 37.0(10), 31.8(11), 29.4, 29.2 and 28.9
(12, 13, 14), 25.0 (15), 22.6 (16), 14.0 (17)
However, the numbers in parentheses indicate the following carbons. Example 2 Meso-tetra [α, α,
0.33 gr of α,α-(O-stearoylamidophenyl)]porphine was dissolved in 25 ml of dry tetrahydrofuran and replaced with _N2 . To this was added 0.1 ml of 2,6-lutidine, then 0.3 gr of ferrous bromide (FeBr ₂ ).
was added and heated to reflux. 2 hours later, more
Add 0.1 gr of FeBr ₂ , heat for 2 hours, evaporate to dryness, and remove the remaining solid using chloroform as the eluent solvent.
Purification was performed using a basic alumina column, and 0.2 ml of concentrated HBr was added to the effluent, followed by shaking and washing with water. The chloroform layer was dehydrated with Na ₂ SO ₄ , evaporated to dryness, and once dried under reduced pressure. This was purified by gel column (BioBeads SX-8, benzene). Thin layer chromatography (Merck silica gel plate, benzene/ether = 1/1): Rf = 0.89 (monospot). Electric field desorption mass spectrum measurement: M+1=
₁₄₅₇ (molecular weight _{of C92H120N8O4Fe1 1456} ) _. Elemental analysis value (weight%): C71.50 (71.9), H7.61 (7.8), N7.03
(7.3) However, the values in parentheses indicate calculated values for C ₉₂ H ₁₂₀ N ₈ C ₄ FeBr. Infrared absorption spectrum (KBr disc, cm ^-1 ): 2930, 2860 (Vas, Vs
(CH ₂ )), 1680 (Amide I absorption band), 1580 (V _C=C (phenyl nucleus), 760 (δCH ₂ (out-of-plane) (O-substituted phenyl nucleus). Example 3 Synthesized in Example 2 Iron-meso-tetra [α,
α,α,α-(O-stearoylamidophenyl)]porphin・Br 3×10 ^-6 mol and 1,
2-dimethylimidazole (hereinafter referred to as 1,2-
After dissolving 1.5×10 ^-7 mol of toluene (denoted as DMeIm) in 7 ml of toluene and purging with N ₂ gas, 5 ml of water containing excess NaS ₂ O ₄ was added, thoroughly shaken, and allowed to stand. The benzene layer was separated and dehydrated with deoxygenated Molecular Sigos 4Å, and the desired Fe()porphyrin complex (corresponding to formula (C)) was dried with benzene (however,
10 ^-4 M water) solution was prepared. This visible absorption spectrum is shown by curve a in FIG. This is a five-coordinated deoxy complex with λmax of 560 nm and 535 nm (shoulder), namely Fe()-meso-tetra[α,
α,α,α-(O-stearoylamidophenyl)]porphine-mono(1,2-dimethylimidazole) complex. When oxygen gas was brought into contact with this, a change in the spectrum was immediately observed.
λmax 549 nm (oxygen complex) was obtained (curve b). From the time course of the visible absorption spectrum, the stability of this oxygen complex at 25°C was over 20 minutes. Also,
The stability of this oxygen complex at -10°C was over 1 hour. Example 4 A Fe()deoxy complex solution was prepared in the same manner as in Example 3, except that benzene was used instead of toluene and 0.1 gr of poly(styrene) was added. This was freeze-dried to remove benzene and obtain polystyrene particles in which the complex was dispersed. To this, 10 ml of nitrogen gas saturated water was added to prepare solid particle dispersion water. As shown in curve c in Figure 2, under _N2 , the 5-coordinated deoxy form (Fe
Spectrum corresponding to ()-meso-tetra[α,α,α,α-(O-stearoylamidophenyl)]porphine-mono-(1,2-dimethylimidazole) complex) (λmax 560 nm, 532 nm (shoulder))
I got it. When O ₂ gas was introduced into this solid dispersion water,
Spectrum of immediately oxygenated complex (λmax550nm)
(curve d). When CO gas was introduced into this, a spectrum (λmax 530 nm) corresponding to the Fe()CO complex was immediately given (curve e). 25℃,
The stability of the oxygen complex in water was more than 10 hours. Example 5 5,10,15,20-tetra(α,α,α,α-( O-cyclohexanoylamidophenyl))porphyrin was synthesized. Elemental analysis value (weight%): C77.13 (77.6, H6.71 (6.6),
N10.22 (10.1) However, the values in parentheses are C ₇₂ H ₇₄ N ₈ O ₄
The calculated value for is shown. Electric field desorption mass spectrum: M+1=1115 (molecular weight 1114). Example 6 A central iron was introduced into the 5,10,15,20-tetra(α,α,α,α-(O-cyclohexanoylamidophenyl))porphine synthesized in Example 5 according to Example 2. . Elemental analysis value (weight%):
C68.87 (69.2), H5.71 (5.8), N8.82 (8.9), however,
Values _in parentheses indicate calculated values _{for C72H74N8O4FeBr .} Example 7 5,10,15,20-tetra (α, α, α, α
After synthesizing -(O-phenylacetylamidophenyl))porphyrin, a central iron was introduced according to Example 2. Electric field desorption mass spectrum: M+1=
1200 (molecular _{weight of C76H56N8O4Fe} 1200) _. Elemental analysis value (weight%): C70.92 (71.3, H4.65 (4.4), N8.41
(8.8). However, the numbers in parentheses are
Calculated values for C ₇₂ H ₅₆ N ₈ O ₄ FeBr are shown. Example 8 In Example 1(B), serotoyl chloride (

[Formula]) The same reaction was carried out and purified except that 5.0gr was used.
Elemental analysis value (weight%): C81.53 (81.21, H10.61
(10.7), N5.02 (5.1), values in parentheses are
Calculated values of C ₁₄₈ H ₂₃₄ N ₈ O ₄ are shown. A central iron was introduced into this according to Example 2. Elemental analysis value (weight%): C76.18 (76.6), H10.37 (10.1), N4.81 (4.8)
,
However, the values in parentheses indicate calculated values for C ₁₄₈ H ₂₃₂ N ₈ O ₄ FeBr. Example 9 (A) Meso-tetra (α, α, α,
α-o-arachidoylamidophenyl)porphine was synthesized. Elemental analysis value (weight%):
C79.43 (79.22), H8.66 (8.84), N7.01 (7.39) (However, the values in parentheses indicate the calculated values for C ₁₀₀ H ₁₃₈ N ₈ O _4. ) (B) Example 2 In, meso-tetra (α, α,
Iron-meso-tetra (α, α, α, α-o −Arachidoylamide phenyl)porphyrin・
Synthesized Br. Elemental analysis value (weight%): C72.30
(72.79), H8.53 (8.31), N6.50 (6.79), (However, the values in parentheses indicate the calculated values for C ₁₀₀ H ₁₃₆ N ₈ O ₄ FeBr) Example 10 Examples 6 and 7 The stability of the oxygen complex was evaluated in the same manner as in Examples 3 and 4 using the iron porphyrin complexes synthesized in , 8 and 9. The results are shown in Table 1 below.

【table】

【table】 [Brief explanation of drawings]

FIGS. 1 and 2 are graphs showing visible absorption spectra of the porphyrin iron complex of the present invention before and after oxygenation.

Claims (1)

[Claims] 1. General formula (Here, R is an alkyl group having 17 to 25 carbon atoms, a benzyl group, or a cyclohexyl group), or its iron ion coordination complex, or its iron ion
A complex that is in a valent state and has a basic axial ligand coordinated to it. 2. The complex according to claim 1, wherein the basic axial ligand is an imidazole derivative or a pyridine derivative.