WO2006001430A1 - PORPHYRIN COMPOUND HAVING α3β SUBSTITUTION STRUCTURE, METAL COMPLEX THEREOF AND OXYGEN INFUSION CONTAINING SAME - Google Patents

Abstract

Disclosed is a porphyrin compound represented by the formula [I] below or a metal complex thereof. In the formula [I] below, R1 represents an optionally substituted alicyclic hydrocarbon group and R2 represents an axial base coordinating group represented by the formula [II] below or the like.

Description

An α ³ j3 substituted structure of Borfilin compound or a metal complex thereof, and an oxygen infusion containing the same

 Technical field

 [0001] The present invention relates to a borfilin compound or a metal complex thereof that can be used as an artificial oxygen carrier, and an inclusion compound containing the compound.

 Background art

 [0002] Heme, the active center of hemoglobin and myoglobin that plays a role in the transport and storage of oxygen in the body, that is, porphyrin iron (II) complex, absorbs molecular oxygen reversibly in response to oxygen partial pressure. Detachable. Many studies have been reported for a long time to realize such oxygen bond dissociation ability similar to that of natural heme with synthetic porphyrin iron (II) complexes. For example, JP Collman, Acc. Chem. Res., 10, 265 (1977), F. Basolo, BM Hoffman, J. A. Ibers, Acc. Chem. Res., 8, 384 (1975), etc. Recent research examples are summarized in Momenteau et al., Chem. Rev., 94, 659 (1994) and JP Collman et al., Chem. Rev., 104, 561 (2004).

 In particular, it has been reported that stable oxygen complexes can be formed under room temperature conditions!

(Ii) As a complex, 5, 10, 15, 20-tetrakis (a, a) of _α ⁴ structure in which a pibaylol group is introduced in the same direction with respect to the porphyrin plane in the amino group of tetrakis o aminoporphyrin , a, α-o pivalamide phenol) porphyrin iron (II) complex (hereinafter referred to as FeT pivPP complex) (JP Collman, et al "J. Am. Chem. Soc, 97, 1427 (1975)) The FeTpivPP complex can be used in an organic solvent such as benzene, toluene, dichloromethane, tetrahydrofuran, N, N dimethylformamide at room temperature in the presence of an excess axial base such as 1 alkyl imidazole, 1 alkyl 2-methylimidazole, etc. Oxygen molecules can be adsorbed and desorbed reversibly, and if this complex is embedded in a bilayer vesicle composed of phospholipids, the same applies even under physiological conditions (aqueous phase, pH 7.4, 37 ° C). Exerts its oxygen bond dissociation ability That (e.g., E. Tsuchida et al., J. Chem. Soc, Dalton Trans., 1984, 1147 (1984), etc.). [0004] However, in order for the FeTpivPP complex to reversibly bind oxygen, it is necessary to add an excess number of axial base ligands to the external force as described above. Some imidazole derivatives widely used as axial base ligands have pharmacological effects and are often highly toxic in the body. In addition, when phospholipid endoplasmic reticulum is used, an excessively coexisting imidazole derivative may be a factor destabilizing the form. The method for limiting the amount of this axial base ligand added to the limit is to introduce an imidazole derivative via a covalent bond into the molecule.

 [0005] The present inventors can supply a stable oxygen carrier without external addition of an axial base by covalently bonding an imidazole derivative as a side chain substituent into the porphyrin iron (II) complex molecule. In this way, we synthesized a FeTpivPP analog having a substituent at the 2-position of the porphyrin ring, and prepared a clathrate compound containing this in human serum albumin in the phospholipid endoplasmic reticulum. It is provided as an artificial oxygen carrier that can be adsorbed and desorbed (Japanese Patent Laid-Open No. 59-164791, Japanese Patent Laid-Open No. 59-162924, Japanese Patent Laid-Open No. 6-271577, Japanese Patent Laid-Open No. 8-301873, JP 2003-040893). In addition, we clarified that the stability of the oxygen complex of the borphyrin metal complex albumin clathrate compound in which the axial coordination ligand histidine derivative is introduced at the 2-position of porphyrin is greatly increased compared to the case of the imidazolylalkyl group. (T. Komatsu, et al "Bioconjugate Chem., 13, 397 (2002)).

 However, in order to synthesize such porphyrin iron (II) complexes, it is necessary to construct a substituent that functions as an axial base at the 2-position of the porphyrin ring. Since this was a step-by-step synthesis process, this was the biggest factor in reducing the overall yield by force if it took time to prepare.

[0007] Furthermore, an imidazolylalkyl group as an axial base ligand was bonded to one of the amino groups of tetrakis-o-aminoporphyrin, and a hydrophobic substituent was bonded to the other three amino groups. Examples of porphyrin metal complexes include JP Collman et al., J. Am. Chem. Soc, 10 02, 4182 (1980) and 5- (imidazolylalkylenamide phenol) 1, 10, 15, 20 tris (pivalamide phenol- Le) Borhu Irinato iron is described. However, these vorphiline derivatives are obtained by first attaching three bivaloyl groups to tetrakis o-, a, a, α-aminophenol-porphyrin and then atropisomerizing the remaining one amino group. (Ie a β structure) and imidazolyl groups are synthesized in order, and the total yield is as low as 5% or less. In addition, since the hydrophobic substituent of this porphyrin metal complex is a bivaloyl group, it is not possible to sufficiently cover the vicinity of the oxygen coordination locus with only three, so that even if a small amount of water coexists, it is immediately oxidized and the oxygen complex is formed. Cannot be formed.

 Disclosure of the invention

[0008] Accordingly, the present invention eliminates the above-mentioned problems of the prior art and efficiently produces a stable oxygen complex that effectively acts as an oxygen infusion solution with a smaller number of steps. Therefore, the tetrakis-amino-phenol is used. The object is to provide a novel α ³ 18-substituted porphyrin metal complex in which an axial base ligand is introduced into one amino group of porphyrin and a hydrophobic substituent is introduced into the remaining three amino groups.

[0009] In order to obtain a porphyrin metal complex that forms a stable oxygen complex more easily, the present inventors have conducted extensive research on the molecular design and improvement of the synthesis process. As a result, the tetrakis-ο-aminophenol was obtained. An axial base ligand was introduced into one amino group of porphyrin, and an alicyclic hydrocarbon group was introduced into the remaining three amino groups. (The porphyrin metal complex with an X ³ β-substituted structure has been much shorter than before. It was found that a porphyrin metal complex satisfying the structural requirements can be obtained by having an axial base and a hydrophobic locating group in the conventional synthesis process, and the present invention has been completed.

 [0010] That is, according to the first aspect of the present invention, the formula [I]:

 [Chemical 1]

Formula [I]

(Where R is an alicyclic hydrocarbon group which may have a substituent, and R is a group represented by the formula [II]: [Chemical 2] Formula [

 (Where R is an alkylene group, R is a coordinated transition metal ion M of the 4th to 5th periods of the periodic table)

 3 4

 Group that allows coordination of the imidazolyl group to the transition metal ion M) or a compound of the formula [II

1] ：

 [Chemical 3]

Formula [III]

 (Where R is a group on the carbon at the ex position of the carboxyl group of the amino acid, R is a hydrophobic group, X

 5 6 is an axial base coordinating group represented by 0 or 1), or a porphyrin compound represented by

The metal complex coordinated with five periods of transition metal ions is provided.

[0014] According to the second aspect of the present invention, there is provided a porphyrin metal complex-albumin inclusion complex obtained by including the porphyrin metal complex of the present invention in albumin.

[0015] Furthermore, according to the third aspect of the present invention, there is provided an artificial oxygen carrier comprising the porphyrin metal complex-albumin inclusion compound of the present invention as an active ingredient.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0016] The Borfilin compound of the present invention is represented by the above formula [I].

 [0017] In the formula [I], R represents an alicyclic hydrocarbon group which may have a substituent. Such alicyclic

 1

The preferred hydrocarbon group is preferably an alicyclic hydrocarbon group having a substituent at the 1-position, which can effectively bring the central part of the relatively bulky Borfilin compound into the hydrophobic atmosphere. Examples of such an alicyclic hydrocarbon group having a substituent at the 1-position include 1-substituted cyclopropyl group, 1-substituted cyclopentyl group, 1-substituted cyclohexyl group, 1-methyl 2-cyclohexyl. Group, 2-substituted norbornyl group, 1-adamantyl group, 1 Examples of the position substituent include a methyl group, an alkylamide group (RCONH), an alkyl ester group (ROOC), and an alkyl ether group (RO). Here, the alkyl group represented by R is preferably a C to C alkyl group.

 1 6

 [0018] In the formula [I], R is an axial base coordinating group represented by the above formula [II] or the above formula [III].

 2

In the formula [II], R is an alkylene group, preferably a C to C alkylene group. R is

 3 2 18 4 Coordination of the imidazolyl group to the central transition metal ion M is allowed when the transition metal ion M in the 4th to 5th periods of the periodic table is coordinated to the borfilin compound of formula [I] It is a group (does not inhibit coordination). Examples of such R are hydrogen atom, methyl group, ethyl group or

 Four

 It is a mouth pill group.

 [0020] In the formula [III], R represents glycine, alanine, valine, leucine, isoleucine, serine,

 Five

 The carboxyl group of amino acids (HOOCC (R) NH) such as leonine and phenylalanine

 5 2

 Group on the carbon at the position. R is a hydrophobic group such as hydrogen, acetyl group, benzyl

 6

 An oxycarbonyl (Boc) group, and a t-butyloxycarboxyl (Z) group.

[0021] The present invention also provides a porphyrin metal complex in which a transition metal ion M in the 4th to 5th periods of the periodic table is coordinated to the borfilin compound of the formula [I]. The transition metal ion M is preferably Fe or Co. The valence of Fe can be +2 or +3, and the valence of Co can be +2. This porphyrin metal complex can be represented by the formula [IV].

 [Chemical 4]

Formula [IV]

[0022] In the formula [IV], X— represents a halide ion such as a chloride ion or a bromide ion. The number n of X— is the number obtained by subtracting 2 from the valence of the transition metal ion M.

In the porphyrin metal complex of the present invention, when the central metal ion M is +2, the imidazole group bonded in the molecule coordinates to the porphyrin central metal M as a proximal base. This state can be expressed by the following formula [V]. In Formula [V], the imidazole group coordinated to the central metal M corresponds to the imidazole group in Formula [II] or Formula [III]. For simplicity, the R group in Formula [II] is excluded. It is. In addition, it was bonded to the ortho position of phenyl.

 Four

 The wavy line connecting nitrogen and the imidazole group represents the residue in the formula [II] or [III] except the imidazole ring.

 [Chemical 5]

[0024] When this imidazole group is coordinated to the central metal M, the oxygen-binding ability can be exhibited only by the Borfilin complex molecule. Thereby, it is not necessary to add an imidazole derivative excessively as an axial base ligand. Furthermore, an imidazole group can be bonded into the molecule without introducing a substituent at the 2-position of the porphyrin. This metal complex can form a stable oxygen complex in water when included in albumin such as ushi serum albumin, human serum albumin, recombinant human serum albumin, albumin multimer, etc. The function of Inclusion of the metal complex into albumin can be performed using, for example, the technique described in JP-A-2003-040893.

[0025] If the porphyrin is a complex of a metal ion belonging to the fourth period, for example, the added value as a catalyst for the oxidation-reduction reaction, oxygen oxidation reaction or oxygen addition reaction is also high. Therefore, the porphyrin metal complex of the present invention includes an artificial oxygen carrier, a gas adsorbent, an acid It will also have features as a catalytic reduction catalyst, oxygen oxidation reaction catalyst, and oxygen addition reaction catalyst.

[0026] Artificial oxygen carriers can be used as a substitute for blood for transfusion, preoperative blood diluent, supplemental fluid for extracorporeal circuit such as artificial heart and lung, perfusion fluid for transplanted organ, oxygen to ischemic site Supply fluid, chronic anemia treatment agent, liquid ventilation perfusate, sensitizer for cancer treatment, culture solution of regenerative tissue cells, use for rare blood group patients, response to transfusion refusal patients for religious reasons, Application to animal medicine is expected. The artificial oxygen carrier is obtained by dispersing the porphyrin metal complex albumin inclusion complex of the present invention in physiological saline. The concentration of the porphyrin metal complex albumin inclusion complex varies depending on the application, but a blood substitute of about 9.2 mmol ZL can be used as a blood substitute, and other concentrations can be used.

 [0027] The method for producing the borfilin compound of the present invention is not particularly limited. For example, a mesotetrakis (a, a, a, α-o aminophenol) porphyrin represented by the following formula [VI] is used. It can be synthesized as a starting material.

 [Chemical 6]

Formula [VI]

[0028] Specifically, meso-tetrakis (a, a, a, α-o aminophenol) porphyrin is dissolved in an appropriate organic solvent (for example, black form, tetrahydrofuran, etc.), and trityl bromide is dissolved therein. Add triethylamine and stir for another 10 minutes to 1 hour, and then remove the solvent under reduced pressure. Add the obtained porphyrin solution in toluene to a container containing activated alumina and heptane, and stir at 90 ° C for 12-24 hours in the dark. Alumina is filtered off with a glass filter, and mesotri (a, a, α-o aminophenyl) porphyrin is fractionated and purified by a silica gel column (o- (N triphenylmethyl) aminophenyl) porphyrin. Obtained po A solution of rufilin and a suitable base (pyridine, 4-dimethylaminopyridine, triethylamine, etc.) in a suitable organic solvent (eg, chloroform, tetrahydrofuran, etc.)

 1

A nitrogen atmosphere is added dropwise to the acid chloride represented by COC1 (where R is as defined above).

 1

 Stir at room temperature for 2-15 hours. After removal of the solvent under reduced pressure, chloroform and water are added, the aqueous layer is washed with chloroform and the organic layer is recovered, and the solvent is removed under reduced pressure. The resulting residue was fractionated and purified on a silica gel column and dried in vacuo to give mesotriol (α, a, ao (cycloalkanamide)) (β-ο- (Ν triphenylmethyl) aminophenol. -Le) Obtain porphyrin as a solid. A solution in which the obtained porphyrin and an appropriate base (pyridine, 4-dimethylaminopyridine, triethylamine, etc.) are dissolved in an appropriate organic solvent (eg, black-form form, tetrahydrofuran, etc.) is used as the following formula [VII] or [ VIII] in the acid chloride of ω imidazolyl carboxylic acid (wherein R to R are as defined above in formula [VII] or formula [VIII])

 3 6

 Add dropwise and stir at room temperature for 2-15 hours under nitrogen atmosphere.

 [Chemical 7] Shikinen

Formula [VIII]

[0029] Thus, after removing the solvent under reduced pressure, the chloroform layer is washed with water and the solvent is removed under reduced pressure. The obtained residue is fractionated and purified by a silica gel column and dried in a vacuum, whereby a porphyrin compound represented by the formula [I] can be obtained.

[0030] Introduction of the central metal to the thus obtained Borhuyrin compound is achieved by a general method described in, for example, D. Dolphin, The Porphyrin, 1978, Academic 'Press, etc., and as a corresponding porphyrin metal complex can get. In general, porphyrins in the case of iron complexes When the iron (m) complex is a cobalt complex, a porphyrin cobalt (π) complex is obtained.

[0031] Among the above porphyrin metal complexes, when they are in the form of iron (in) complexes, an appropriate reducing agent (sodium nithionite, ascorbic acid, etc.) is used, and the central metal is trivalent to divalent by a conventional method. If reduced to oxygen, oxygen binding activity can be imparted. These porphyrin iron (II) complexes are systematically encapsulated in human serum albumin, system encapsulated in recombinant human serum albumin, system encapsulated in albumin polymer, and in any case, stable immediately when contacted with oxygen A simple oxygen complex. Further, these complexes can adsorb and desorb oxygen according to the oxygen partial pressure. This oxygen bond dissociation can be repeated reversibly and acts as an oxygen adsorption / desorption agent and oxygen carrier.

[0032] In the case of a gas that is coordinated to a metal other than oxygen, a corresponding coordination complex can be formed (for example, carbon monoxide, nitrogen monoxide, etc.). For these reasons, the porphyrin metal complex of the present invention is a free imidazole with high body toxicity that can be applied as a redox reaction catalyst and gas adsorbent in homogeneous and heterogeneous systems. The iron (II) or cobalt (II) complex has characteristics as an artificial oxygen carrier because it can be easily synthesized by eliminating its existence.

 Hereinafter, the present invention will be described in detail with reference to some examples. Needless to say, the present invention is not limited to these examples.

[0034] Example 1

All the steps were performed under light shielding. In a 500 mL three-necked flask, add a mixture of atropisomers of mesotetrakis (o-aminophenol) porphyrin (1.99 g, 2.97 mmol), triethylamine (1.2 mL) and 200 mL of black mouth form. The mixture was stirred for 15 minutes under a nitrogen atmosphere. Thereto was added 30 mL of a chloroform solution of trityl bromide (1.OOg, 3.lOmmol), and the mixture was stirred at room temperature for 15 hours, and then the solvent was removed under reduced pressure. Next, 300 mL of heptane and 116 g of alumina were added to a 1 L three-necked flask, and the mixture was refluxed and stirred for 2 hours in a nitrogen atmosphere. Thereto was added a toluene solution (50 mL) of porphyrin reacted with the above trityl bromide, and the mixture was stirred under reflux for 14 hours. After completion of the reaction, the supernatant is removed, the alumina is washed with an acetone Z methanol mixture solution (acetone Z methanol = 10,1 (v / v)), the adsorbed volfilin is eluted and recovered, and the solvent is removed under reduced pressure. did. This is a silica gel column Z-ethyl acetate = iZi (vZv)), the first and second components with low polarity are removed, the mobile phase is changed to black mouth form Z acetone = 7Zl (v / v), and the eluted components The product was dried under vacuum to obtain messortry (a,, α-o aminopheniniole) j8-o- (N triphenyl-amino) aminophenol-porphyrin as a purple solid in a yield of 840 mg (57% yield).

[0035] <Analysis results>

 Thin layer chromatography (black mouth form Z ethyl acetate = lZl (volume / volume): Rf: 0.33 (monospot)).

 [0036] UV-visible absorption spectrum (Kuroguchi Holm, λ = 420, 517, 550, 590, 647 nm)

 max

 FAB — MS spectrum (m / z): Calculated for C H N: 916.40; Found: 916.40 [M

 63 48 8

 + H] +.

 [0037] ^ H—NMR ^ vector (CDC1, TMS standard, δ (ppm):-2.6 (s, 2H, internal H), 5.2 (s,

 Three

 1H, -NHC (Ph)), 6.7-7.3 (m, 12H, Ph), 8.9 (d, 8H, pyrrole-j8).

 Three

 [0038] Example 2

 Add 1-methylcyclohexanoic acid (1.40 g, 9.88 mmol) and 5 mL of chloroform to a 500 mL three-necked flask and stir for 20 minutes at room temperature in a nitrogen atmosphere. Then add 4 mL of oxalyl chloride and stir for 2 hours. did. After confirming the formation of acid chloride from the infrared absorption spectrum power, chloroform and hydrochloride were removed under reduced pressure to obtain 1-methylcyclohexanoic acid chloride. Then, the mesotri, a, α-o aminophenol) synthesized in Example 1—j8—o— (N triphenyl) aminophenol porphyrin (840 mg, 14 mmol), 4 dimethylaminopyridine (1.7 g, 14 mmol) of 50 mL of a black mouth form solution was slowly added dropwise using a dropping funnel, and the mixture was stirred at room temperature under a nitrogen atmosphere for 15 hours. Thereto was added 15 mL of methanol, and after stirring for 15 minutes, the solution was removed under reduced pressure, extracted with chloroform, washed with water, dehydrated with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was fractionated and purified on a silica gel column (black-form Z-ethyl acetate = 20 Zl), dried in vacuo and mesotri (a, a, a — o- l-methylcyclohexamide phenol as a purple solid. ) — (Β—ο— (Ν-trimethyl) aminophenol) porphyrin was obtained in a yield of 787 mg (yield 67%).

[0039] <Analysis results>

Thin-layer chromatography (Black mouth form Z Ethyl acetate = 20Zl (volume Ζvolume): Rf: 0. 55 (mono spot)).

 [0040] Infrared absorption spectrum (cm—: 1688 (v, amide)

 c = o

 UV-visible absorption spectrum (Kuroguchi Holm, λ = 416, 513, 546, 587, 642 nm)

 max

 NMR ^ vector (CDC1, δ (ppm)): —2.8 (s, 2H, internal H), 0.0 (s, 9H, -Me),

 Three

 0.0-0.5 (m, 24H, cyclohexyl) 4.8 (s, 1H,-NH- C (Ph)), 6.6 (m, 17H, Ph), 7.

 Three

 0-8.8 (m, 24H, ferrule, pyrrole-j8, amide)

 FAB — MS spectrum (m / z): Calculated for C H N O: 1289.7; Actual value: 1289.7 [

 87 84 8 3

[0041] Example 3

 6-Bromohexanoic acid (1. Og, 5.35 mmol) and oxalyl chloride (0.7 mL) were added to a 50 mL three-necked flask, and the mixture was stirred at room temperature for 3 hours, and oxalyl chloride was removed under reduced pressure. Thereto was added dropwise a solution of biphenyl-carbinol (1.29 g, 7.02 mmol) and triethylamine (1 mL) in black mouth form (5 mL), and the mixture was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere. After removing the solvent under reduced pressure, extraction with Kuroguchi Form was performed, followed by washing with water, dehydrating with anhydrous sodium sulfate, and removing the solvent under reduced pressure. This was fractionated on a silica gel column (CHC1) and then vacuum-dried to obtain a pale yellow liquid.

 Three

 6-bromohexanoic acid diphenylmethyl ester was obtained in a yield of 1.57 g (yield 80%).

 [0042] <Analysis results>

 Thin layer chromatography (black mouth form): Rf: 0.71 (monospot)).

 [0043] Infrared absorption spectrum (cm—: 1730 (V, ester)

 c = o

 ^ Η— NMR ^ vector (CDC1, TMS standard, δ (ppm)): 1.3 (m, 2H,-CH CH-C (= 0

 3 2 2

)-), 1.6 (m, 2H, Br- (CH) CH-), 1.8 (m, 2H, BrCH CH-), 2.3 (t, 2H, Br— CH-)

 2 2 2 2 2 2

, 3.2 (t, 2H, — CH— C (= 0) —), 6.9 (s, 1H,-CH (Ph)), 7.2-7.4 (m, 10H, —Fail)

 twenty two

 FAB — MS spectrum (m / z): Calculated for C H O Br: 360.08; Found: 360.07

 19 21 2

 [M] +.

[0044] Example 4

2-Methylimidazole (236 mg, 2.87 mmol) recrystallized and purified from benzene was dissolved in 10 mL of dimethylformamide, and the 6-bromohexanoic acid diphenol synthesized in Example 3 was used. Chiller ester (333 mg, 0.921 mmol) was added, and the mixture was stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure, extracted with chloroform, washed with water, dehydrated over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. This was fractionated with a silica gel column (black mouth form Z methanol: 10/1 (volume / volume)), and the resulting components were vacuum-dried to give 6- (2-methylimidazole-1yl) hexanoic acid. Diphenylmethyl ester was obtained as a light brown viscous liquid in a yield of 195 mg (yield 58%).

[0045] <Analysis results>

 Thin layer chromatography (black mouth form Z methanol = 10 Zl (capacity Z capacity): Rf: 0.49 (monospot)).

 [0046] Infrared absorption spectrum (cm—: 1730 (V, ester)

 c = o

 NMR ^ vector (CDC1, TMS standard, δ (ppm)): 1.3 (m, 2H, — CH— CH— C (=

 3 2 2

○)-), 1.7 (m, 4H,-(CH) (CH) C (= 0)-), 2.3 (s, 3H, — CH), 2.4 (t, 2H, N— CH-)

 2 2 2 2 3 2

, 3.7 (t, 2H, — CH 2 —C (= 0)-), 6.7 (s, 1H, — CH (Ph)), 6.9 (2H, br, imidazole), 7.

 twenty two

 2-7.3 (m, 10H, -Fail)

 FAB — MS spectrum (m / z): Calculated for C H N O: 362.47; measured value: 363.41 [

 23 26 2 2 [0047] Example 5

 Dissolve 6- (2 methylimidazole-1-yl) hexyl methyl ester (195 mg, 0.54 mmol) obtained in Example 4 in 3 mL of acetic acid and stir for 2 hours while bubbling hydrogen chloride gas. After removing hydrochloric acid and acetic acid under reduced pressure, the residue was dissolved in water and washed with ether. The aqueous layer was freeze-dried to obtain 103 mg (yield 87%) of 6- (2 methylimidazole-1-yl) hexanoic acid as a light brown solid.

[0048] <Analysis results>

Infrared absorption spectrum (cm " ¹ ): 1722 (ν, carboxylic acid)

 c = o

 ^ Η—NMR ^ vector (CD OD ゝ TMS standard, δ (ppm)): 1.3-1.4 (m, 2H,-CH CH-

3 2 2

C (= 0)-), 1.7 (m, 2H, — CH (CH) — C (= 0) —), 1.9 (m, 2H, N— CH CH-), 2.4 (t, 2H

 2 2 2 2 2

 , N-CH-), 2.7 (s, 3H, -CH), 4.2 (t, 2H, — CH—COOH), 7.5 (1H, m, imidazole

2 3 2

), 7.6 (1H, m, imidazole) FAB — MS spectrum (m / z): Calculated for CHNO: 196.25; Found: 197.37 [

 10 16 2 2 [0049] Example 6

 In a 50 mL three-necked flask, add 6- (2-methylimidazole-1-yl) hexanoic acid (103 mg, 0.63 mmol) obtained in Example 5 and 6 mL of oxalyl dichloride under a nitrogen atmosphere. After stirring at room temperature for 8 hours, a white solid was obtained by drying under reduced pressure. To the other 50 mL of triflasco, the mesotriol obtained in Example 2 (a, a, α— o— (1-methylcycloquinamide)) j8— o— (N triphenyl-methyl) aminophenol porphyrin ( 200 mg, 0.155 mmol) and 30 mL of chloroform were added and stirred for 15 minutes while blowing hydrogen chloride gas. At this time, the color of the solution changed from magenta to green. Pure water and sodium hydrogen carbonate were added to adjust the pH to 7, followed by extraction with black mouth form, washing with water, dehydration with anhydrous sodium sulfate, and removal of the solvent under reduced pressure to obtain a purple solid. Acetonitrile (20 mL), benzene (2 mL), and dimethylaminopyridine (732 mg) were added to this and added dropwise to the previously prepared 6- (2-methylimidazole 1) hexanoic acid chloride at room temperature under a nitrogen atmosphere. Stir for 15 hours. After removing the solvent under reduced pressure, extraction with black mouth form, washing with water, dehydrating with anhydrous sodium sulfate, and removing the solvent under reduced pressure. This was fractionated and purified on a silica gel column (black mouth form Z ethyl acetate = 10/1 (volume Z volume)) to obtain messortry (α, α, α— o— 1 methyl cyclohexaneamide phenol as a purple powder. ) One (/ 3-0-6-(N- (2-methyl 1-imidazolyl)) hexamide phenyl) porphyrin was obtained in a yield of 158 mg (yield 83%).

[0050] <Analysis results>

 Thin layer chromatography (black mouth form Z methanol = 8Zl (capacity Z capacity): Rf: 0.46 (monospot))

Infrared absorption spectrum (cm " ¹ ): 1686 (V, amide)

 c = o

 UV-visible absorption spectrum (Kuroguchi Holm, λ = 420, 514, 544, 588, 643 nm)

 max

 NMR ^ vector (CDC1, δ (ppm)): —2.8 (s, 2H, internal H), —0.2 (s, 9H, methyl

 Three

 Rucyclohexyl), -0.1- 1.0 (m, 30H, cyclohexyl), 1.2 (t, 2H,-N- CH-CH-

twenty two

), 1.4 (s, 3H, N = C (CH) Ν), 1.9 (m, 4H, — N-CH-(CH)-), 2.6 (m, 2H, CH— CH

 3 2 2 2 2 2

— CH 2 -CO-NH), 5.7 (s, 1H, Imidazole-H), 6.0 (s, 1H, Imidazole-H), 7.0-8. 5 (m, 22H, N—H (amide), phenol), 8.5-8.8 (m, 8H, pyrrole-FAB—MS spectrum (m / z): Calculated for CHNO: 1225.5662; Found: 122

 78 84 10 4

[0051] Example 7

 Add 47% aqueous hydrobromic acid solution (2 mL) to a 50 mL three-necked flask, stir for 30 minutes under a nitrogen atmosphere, add electrolytic iron (26 mg), and stir at 80 ° C for 2 hours under a nitrogen atmosphere. A light green transparent solution was obtained. The solution was heated to 130 ° C, hydrobromic acid and water were removed by evaporation, and then allowed to cool until the oil bath temperature reached 70 ° C to obtain a light yellow powder of iron (II) bromide. . Here, the mesotriol obtained in Example 6 (a, a, a— o— 1 methylcyclohexaneamide phenol) (j8 —0— 6— (N— (2-methyl-1-imidazolyl)) hexaneamide 4 mL of a tetrahydrofuran solution of (phenol) porphyrin (34 mg ゝ 0.03 mmol) and 2,6-lutidine (48 L, 0.41 mmol) was added dropwise, and the mixture was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere. After confirming the disappearance of fluorescence (ex. 420 nm, em. 650, 750 nm), the solution was allowed to cool to room temperature, dropped into ice water, and centrifuged (7000 g, 20 minutes) to collect the precipitate. did. This was fractionated and purified on a silica gel column (black mouth form Z methanol = 8 Zl (volume / volume)), dried in vacuo, and then dried as a brown powder with mesotri (a, a, α-o 1-methylcyclohexaneamide) 1) (j8—o 6— (N— (2-methyl-1imidazolyl)) hexanamidephenol) porphyrin iron was obtained in a yield of 24 mg (yield 66%).

[0052] <Analysis results>

 Thin-layer chromatography (black mouth form: methanol: 8Z1 (capacity Z capacity): Rf: 0.28 (monospot))

Infrared absorption spectrum (cm " ¹ ): 1686 (V, amide)

 c = o

 UV-visible absorption spectrum (Kuroguchi Holm, X = 419, 507, 576, 647 nm)

 max

 FAB — MS spectrum (m / z): Calculated for C H N O Fe: 1279.4; Found: 1279

 78 82 10 4

[0053] Example 8

In Example 1, 1-methylcyclopentanoic acid was used instead of 1-methylcyclohexanoic acid, and in Example 6, 6- (2-methyl-1imidazolyl) hexanoic acid was used instead of 4 Follow the same procedure as in Examples 1 to 7 except that 1 (1 imidazolyl) butanoic acid is used, and follow meso-tri (a, a, α- o- (1-methyl) cyclopentanamide phenol) 1 j8— o— 4— (N-1—imidazolyl) butanamide phenol-porphyrin iron was synthesized.

[0054] <Analysis results>

 Thin layer chromatography (black mouth form Z methanol = 10Zl (capacity Z capacity): Rf: 0. 5 (monospot))

Infrared absorption spectrum (cm " ¹ ): 1688 (V, amide)

 c = o

 UV-visible absorption spectrum (Kuroguchi Holm, λ = 420, 508, 576, 647 nm)

 max

 FAB — MS spectrum (m / z): Calculated for C H N O Fe: 1194.5; Found: 1194

 72 70 10 4 [0055] Example 9

 In Example 1, 1-adamantanic acid was used instead of 1-methylcyclohexanoic acid, and in Example 6, 10- (2-methyl-1 imidazolyl) decanoic acid was used instead of 6- (2-methyl-1 imidazolyl) hexanoic acid. In the same manner as in Examples 1 to 7, except for using mesotriol (a,, α— o adamantanamide phenol-nor) j8— o— 10— (N— (2-methyl 1 —Imidazolyl)) decanamidophenol-porphyrin iron was synthesized.

[0056] <Analysis results>

 Thin-layer chromatography (black mouth form Z methanol = 20Zl (capacity Z capacity): Rf: 0.5 5 (monospot))

Infrared absorption spectrum (cm " ¹ ): 1689 (V, amide)

 c = o

 UV-visible absorption spectrum (Kuroguchi Holm, λ = 419, 508, 577, 647 nm)

 max

 FAB — MS spectrum (m / z): Calculated for C H N O Fe: 1496.8; Found: 149

 94 108 10 4

 6.7 [M] +.

[0057] Example 10

 Example 1! /, 1 Method using 3-noradamantanecarboxylic acid instead of methylcyclohexanoic acid, and further reacting with cobalt chloride in dry tetrahydrofuran containing 2,6-lutidine in Example 7 In Example 1 except that cobalt is introduced into the porphyrin center.

Follow the same procedure as in step 7, and sort the messortry (α, α, α—ο— 3—noradamantanamide E) β-0-6- (Ν- (2-Methyl-1 imidazolyl)) hexamide phenylporphyrin cobalt was synthesized.

 [0058] <Analysis results>

 Thin layer chromatography (black mouth form Ζ methanol = 15Zl (volume Ζ volume): Rf: 0.4 (monospot))

Infrared absorption spectrum (cm " ¹ ): 1688 (V, amide)

 c = o

 UV-visible absorption spectrum (Chlorophonolem, λ = 403, 521, 552 nm)

 max

 FAB — MS spectrum (m / z): Calculated for C H N O Co: 1353.6; Found: 135

 84 82 10 4 [0059] Example 11

 According to the same procedure as in Examples 1 to 7, except that N-acetyl histidine was used instead of 6- (2 methylimidazole-1-yl) hexanoic acid in Example 6, messortry (a, a, a— o—l-methylcyclohexanamide phenol) 13—o—N acetyl histidine amide phenol porphinate was synthesized.

[0060] <Analysis results>

 Thin layer chromatography (black mouth form Z methanol = 8Zl (capacity Z capacity): Rf: 0.2 (monospot))

Infrared absorption spectrum (cm " ¹ ): 1686 (V, amide)

 c = o

 UV-visible absorption spectrum (Kuroguchi Holm, X = 418, 506, 578, 645 nm)

 max

 FAB — MS spectrum (m / z): Calculated for C H N O Fe: 1327.6; Found: 1327

 79 89 11 5 [0061] Application example 1

Mesotriol synthesized in Example 7 (α, a, α—ο— l-methylcyclohexaneamide phenol)-β -ο-6- (Ν- (2-methyl-1-imidazolyl)) hexaneamide Ferrophyllin iron (111) 0.03 _i umol was purged with 10 mL of anhydrous toluene solution, and then mixed and stirred in a heterogeneous system with an aqueous solution of nitrous acid to reduce it to iron (II). 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, mesotriol (a, a, a-o-l-methylcyclohex A toluene solution of sanamide phenol)-(j8—o—6— (N— (2-methyl-1-imidazolyl)) hexanamide phenol) porphyrin iron (Π) complex was obtained. The visible absorption spectrum of this solution is λ: 427, 532, 559 nm, and the complex is 5-coordinated with one imidazole coordinated max

 It became clear that it was equivalent to the Deoxy type. When oxygen gas was blown into this solution, the spectrum immediately changed and a spectrum of λ: 426, 548 nm was obtained. This is max

 The formation of oxygenated complex was revealed. 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 spectrum, so that it is clear that oxygen adsorption / desorption occurs reversibly. Helped. In addition, by repeating the operation of blowing oxygen and then nitrogen, oxygen adsorption / desorption could be continuously performed. The oxygen affinity (oxygen partial pressure (= P) when 50% of the total porphyrin iron was oxygenated) was 67 Torr (25 ° C).

 1/2

 [0062] Application Example 2

 Mesotriol synthesized according to Example 7 (a, a, α— o cyclohexanamide phenol) mono (j8 — o— 6— (N— (2-methyl-1-imidazolyl)) hexanamide phenol (1) Albumin heme complex (porphyrin Z albumin: 4 (mol / mol) encapsulated in human serum albumin (2.5 / z M) according to the method described in Patent Document 4 mol)) Phosphate buffer solution (pH 7.3) 3 mL was transferred to a quartz spectrophotometer cell and aerated with oxygen, λ was 426, 550 nm, and a visible absorption spectrum was obtained.

 Oxygenated complex formation was shown. When nitrogen gas is blown into this oxygenated complex solution for 1 minute, the visible absorption spectrum reversibly changes to the oxygenated spectral force deoxy type spectrum, and it is clear that the adsorption / desorption of oxygen occurs reversibly. It was. In addition, it was possible to continuously perform oxygen adsorption / desorption by repeating the operation of blowing oxygen and then nitrogen. The oxygen affinity P was 45 Torr. In addition, this oxygen coordination complex gradually deteriorates

 1/2

 The half-life was about 4 hours (37 ° C).

[0063] As described above, the porphyrin metal complex of the present invention is one in which an axial base group ligand is simply introduced into the porphyrin metal complex to provide an excellent oxygen transport capability. The total yield was about 20%, and the target product could be obtained more efficiently than the conventionally reported axial base-bonded porphyrin metal complex with α ³ 18 structure. The porphyrin metal complex is The porphyrin metal complex-albumin inclusion complex encapsulated in serum albumin can be a useful material excellent in biocompatibility when considered for in vivo administration as an artificial oxygen carrier. In addition to the artificial oxygen carrier described above, the porphyrin metal complex of the present invention is useful as a gas adsorbent, an oxygen adsorbing / desorbing agent, a redox catalyst, an oxygen oxidation reaction catalyst, and the like.

Claims

The scope of the claims  Formula [I] Formula [I]

 (Where R is an alicyclic hydrocarbon group which may have a substituent, and R is a group represented by the formula [Π]:  1 2  [Formula 10] Formula [

(Where R is an alkylene group, periodic table R is coordinated with transition metal ions M in the 4th to 5th periods)  3 4 A group that allows coordination of the imidazolyl group to the transition metal ion M) or the formula [II 1]:  [Chemical 11] Formula [m]

 (Where R is the group on the α-position carbon of the carboxyl group of the amino acid, R is a hydrophobic group, X is  5 6 A borfilin compound represented by 0 or 1), or a metal complex thereof coordinated with a transition metal ion of the 4th to 5th period of the periodic table. [2] The porphyrin compound according to claim 1, which is an alicyclic hydrocarbon group having a substituent at the R 1S 1-position. 1  Or its metal complex.  [3] The R force C to C alkylene group or the porphyrin compound according to claim 1 or 2.  3 2 18  Or its metal complex.  [4] R force A hydrogen atom or a methyl group, an ethyl group or a propyl group.  Four  4. The Borfilin compound or the metal complex thereof according to any one of 3. [5] R force hydrogen atom, acetyl group, benzyloxycarbonyl group or tert-butyl  6  The porphyrin compound or the metal complex thereof according to claim 1, which is a carboxy carbonyl group, and the displacement force of 1. [6] The metal complex according to claim 1, which is M force Fe or Co.  7. The metal complex according to claim 6, wherein the valence of Fe is +2 or +3.  8. The metal complex according to claim 6, wherein the Co valence is +2.  [9] A volphiline metal complex albumin clathrate complex comprising the metal complex according to any one of claims 1 and 8 clathrated in albumin. 10. The porphyrin metal complex-albumine inclusion compound according to claim 9, wherein the albumin is ushi serum albumin, human serum albumin, recombinant human serum albumin, or albumin multimer.  [11] An artificial oxygen carrier comprising the porphyrin metal complex-albumin inclusion complex according to claim 10 as an active ingredient.