JPS59162924A - Oxygen adsorbing and desorbing agent - Google Patents

Abstract

PURPOSE:To provide an oxygen adsorbing and desorbing agent capable of reversibly bonding the oxygen molecule in an aqueous medium, a non-protonic solvent or lyposome constituted by using a metal-2-substituted-picketfence porphyrin complex having a specific general formula as a effective component. CONSTITUTION:An oxygen adsorbing and desorbing agent contains a metal-2- substituted-5,10,15,20-tetra[alpha,alpha,alpha,alpha-(o-pivalamide)phe nyl] porphyrin complex represented by general formula I [wherein M is a ferric ion and R is an imidazole derivative group represented by formula II (wherein m is 1 or 2, n is an integer of 3-5, X is -COOH or -CONH and R1, R2 and R3 are respectively independently a hydrogen atom and a methyl group as an effective component and synthesized by a method wherein picketfence porphyrin is converted to an imidazole derivative group added compound through a Cu II complex which is, in turn, converted to an Fe II complex by using FeBr2. The above mentioned Fe II complex is combined with phosphatidyl cholines or phospholipid to make it possible to provide the oxygen adsorbing and desorbing agent suitable for medical purpose high in safety in vivo.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides metal-2-substituted-5,10,15,20-tetra[α,α,α,α-(0-bipalamide]phenyl]
Sakaki, an oxygen adsorbing and desorbing agent containing a porphyrin complex as an active ingredient, relates to an oxygen adsorbing and desorbing agent in which the metal ion has an iron valence and the substituent has an imidazole nucleus at the end.

5.10.15.20-tetra [α, α, α, α-(0
The iron-valent complex of -pipalamide)phenyl]porphyrin (hereinafter referred to as picket fence porphyrin) is active and contains a large molar excess of an axial base such as 1-alkylimidazole or I''i1-alkyl-2-methylimidazole. coexist with benzene, toluene, tetrahydrofuran (hereinafter abbreviated as TfTF), or N,N-dimethylformamide (hereinafter abbreviated as DM).
Abbreviated as F'), oxygen molecules can bind completely reversibly at room temperature in many aprotic solvents (J, P, Col
1man et al.

J, Am, chem, Soc, , 97, 14
27 (1975), ).

Oxygen binding function in the solid state has also been recognized (J,
P, Col1man et al + Pure & Appl,
Chem, +50 +951 (1978), ).

It has recently been reported that a similar function can be exerted in an aqueous medium by encapsulating phosphatidyl phospholipids in liposomes (E, Haae
gawa et al.

Former ochem, former oph) r8. Res+, Com
mun, + 105 + 1416 (1982),)
.

It is possible to retain the properties of iron (It)-Bickett-Fencesporphyrin (hereinafter also referred to as "Pickett-Fencehem"), which has such effective functions, and furthermore, it is possible to maintain the properties of iron (It)-Bickett-Fencesporphyrin (hereinafter also referred to as "Pickett-Fencehem"), and furthermore, it is possible to maintain the properties of iron (It)-Bickett-Fencesporphyrin (hereinafter also referred to as "Pickett-Fencehem"), and furthermore, the metal-2-Bickett-Fensporphyrin (hereinafter also referred to as "Pickett-Fensporphyrin") is fully covalently bonded with imidazole as the proximal base. The availability of substituted picket fence voluphylines, particularly 2-substituted picket fence hems, would provide many more utilities, as described below.

(1) As an axial base, it can function as an active substance with oxygen adsorption and desorption functions without adding an excessive amount of imidazole compounds from the outside.

(2) Lipid-soluble imidazole compounds (hereinafter referred to simply as imidazoles) are preferred as the axial base essential for the expression of the function of picket fence heme, but these have no pharmacological activity. may indicate,
Generally highly toxic in vivo. Covalently bonding imidazole does not require the addition of large amounts of imidazole with the above possibilities.

(3) The active substance consists of imidazole covalently bonded to a high-molecular-weight porphyrin, and its apparent toxicity is low.

(4) The active substance is the only component and the physical properties are constant. For example, in a two-component complex made by mixing picket fence hem and imidazoles, the oxygen adsorption/desorption characteristics tend to change depending on the mixing ratio, but such a drawback can be eliminated.

Therefore, it is an object of the present invention to provide an oxygen adsorbing/desorbing agent containing porphyrin compounds as all active ingredients, which has many more advantages as described above.

51 According to the present invention, M is an iron (IT) ion, R is a formula 6- (where m is 1 or 2, n is an integer from 3 to 5, and
is a metal-2-substituted- imidazole derivative group represented by 1000NH- or -CONH-1R1, R2 and R3 are each independently a hydrogen atom or a methyl group]
5,10,15,20-tetra[α,α,α,α, i.e. according to the invention, among many organic solvents, such as evabenzene, toluene, T[(F By using a solid phase or a surfactant, a material that can completely reversibly adsorb and desorb oxygen molecules in an aqueous medium, such as water, physiological saline, etc., will be provided. In this case, the combination with phosphatidylcholine phospholipids, which are biological components, provides an oxygen adsorption/desorption agent with high in vivo safety.

In the metal-2-substituted picket fence porphyrin complex represented by the general formula used in this invention, M is preferably an iron-valent ion, taking into consideration that it will be administered in vivo; R is 3 and R2 to 21n is 3 to 5. -x- is -0CONH- or -C
It has an imidazole nucleus at the end in the form of -(C■
I2 揄X → CH2 gar group (preferably, the sum of m ten
~7) You must have all of them.

R1-R3 are hydrogen atoms or methyl groups.

The fully condensed-2-substituted-bicket fence porphyrin complex represented by formula (1) can be synthesized, for example, through the following process.

9- ■ 10- CH20H2COO)T When dispersing the metal-2-substituted bicket fence porphyrin complex obtained in this way in an aqueous medium, the surfactant used can encapsulate the above complex in the aqueous medium. Any material may be used as long as a hydrophobic region is secured, but biological components or materials similar thereto are preferred, especially when medical purposes are taken into consideration. For example, egg yolk lecithin, soybean lecithin, dipalmitoylphosphatidylcholine, simyristoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin,
Cholesterol is chosen. These may be used alone or as a mixed component.

As a method for reducing the porphyrin center iron of the above complex to an H-valent form in an organic solvent, for example, benzene, toluene,
Dichloromethane and THFt/c are prepared by adding a small amount of a heterogeneous reduction catalyst, preferably palladium chloride or radium black supported on activated carbon, in an organic solvent such as DMF under a hydrogen stream.
or 13- T. G. Traylor et al., Bioinorg,
chem.
A method of heterogeneous reduction in a two-layer system by adding an aqueous S 204 solution is selected.

An aqueous solution of the iron valence complex is prepared by completely distilling off the solvent from the solution thus obtained and dispersing it in water using the above-mentioned surfactant under oxygen-free conditions.

As a method for reducing in an aqueous medium, for example, E, Has
egawa et al., Biochsm, Biophys,
Res.

Commun., 104.793 (1982), the complex was embedded in phosphatidylcholine phospholipid liposomes and dissolved in dispersed form in water at room temperature. - by adding excess molar amounts of phosphate dehydrodanase, ferredoxin, ferredoxin-NADP -IJ tactase, and catalase, or by the method described in Tsuchida et al., Nikkashi, 255 (1983),
Method 14- is selected, in which ascorbic acid is added in a total amount of about 20 times the amount of ascorbic acid based on the valence complex.

According to this invention, in addition to exhibiting a reversible oxygen adsorption/desorption function in many solvents, many surfactants, such as phosphatidyl phospholipids, can be embedded in the hydrophobic region and can be used in aqueous systems. Since it has similar functional properties even in media, it becomes an oxygen adsorbing and desorbing agent that is convenient for medical purposes.

Next, the present invention will be explained in detail with reference to Examples, but first, synthesis examples of complexes used in this invention will be shown.

Synthesis Example 1゜(11J, P, Colman et al., J, Am, C
hem, Soc, .

Bicket fence porphyrin 20.2 prepared according to the method described in 97.1427 (1975)
9 (20 mmol) f Dissolved in chloroform 1,51, Cu(CH3CO2)2'H206, under boiling point reflux.
Oi (30 mmol) k dissolved methanol saturated m
liquid was added. After refluxing for 30 minutes, the mixture was concentrated under reduced pressure, and methanol was added for crystallization. Recrystallization from chloroform-methanol gave a copper divalent complex of picket fence I ruphyrin (Cu(II)-PFP(H)).

Yield 20.1g (yield 93.8も), melting point (mp)>
300°C TLCRf = 0.49 (silica dull plate, benzene/ether (1/1 (v/v))) IR spectrum (KBr) 1690 (νC=Ol amide)/7
ff' other visible spectrum (CHCz3) λmax 411.534
t568 (shoulder absorption) nm FDMS spectrum rrv/e 1071 (M4 elemental analysis (as C64H64NBO4Cu) Analysis value (calculated value) H: 5.87 (6,01), C near 1.40 (7)
1,65), N;10.29(10,44)chi(:ri
Co(1)-PPP(H) 1 9.0 9
(17.7 mmol) k dichloromethane 1°5
Also dissolved in A'. Separately, DMF'68.5ml (0,
885 mol) and POCl282.51n! (0,8
85 mol) i of the Vilsmeear complex prepared by mixing at room temperature or below under water cooling was added dropwise to the above solution at room temperature over 30 minutes. After boiling under reflux for 8 hours, the temperature was returned to room temperature. After pouring the obtained dark green immonium salt solution into 1.5 liters of ice water, 5,007,111 liters of concentrated ammonia water was added at room temperature and reacted for 1 hour.

Benzene/ether (2/1 (v/v)) H medium k silicatal column (7rrnφX 35c
After purification with m) and recrystallization from acetone-methanol, a steel divalent complex of 2-formyl picket fence porphyrin (C-PFP(CHO)) was obtained.

Yield 12.8g (yield 65.7%), mp260-26
2℃ TLCRf=0.26 (Silica t)”le plate,
benzene/ether (1/1 (v/v)))I
R spectrum (KBr) 1690 (νc=o+amide)
.

1675 (νC=Ol aldehyde) m−1 other visible spectrum (CHC2,) λmax 423, 545.

586 nm FDMS spectrum m/e 1099 (M elemental analysis (as C65H64NBO5Cu1) actual value (calculated value) H: 5.88 (5,86), C near 0.66 (70,
92), N:9.96(10,18)Chi17-(!:D Cu(II)PFP(CHO) 6.O
fJ (5.6 mmol)''f was uniformly dissolved in 120 ml of concentrated sulfuric acid and reacted for 2 hours at room temperature. Under water cooling, 7.
5N-ammonia water/dichloromethane (1/1 (v/
v) ) 1.21.

The residue was washed with water in chloroform M' and dried under reduced pressure, and the residue was purified using a silica dull column (5,5 cfnφX35 m) using a benzene/ether (1/1 (v/v)) solvent. Recrystallized from acetone-methanol to give 2-
Formyl picket fence porphyrin (2H-PFP
(CHO) ) was obtained.

Yield 3.54g (yield 60.9%), mp258~2
60°C TLCRf = 0.44 (silica dull plate, benzene/ether/acetone (8/8/1 (v/v/v)
)) IR spectrum (KBr) 1690 (νc=o
, amide) 1675 (ν, aldehyde) i-1 and other visible spectrum (CHCL3) λmax 429, 521° 559.599.655 nm FDMS spectrum rn/e 1038 (M”?)
Elemental analysis (as C65H66N805) 18- Actual value (calculated value) H: 6.16 (6,40), C near 4
．． 83 (75,12), N: 10.65 (10,78)
Chi PMR spectrum (Cr) Cf3) δ (ppm) -2
,41(-double line, 2H, virol N-H), 0
．． 068, 0.120°0.125 (each - double line,
36H, -CH5), 7.09~s, s7 (multi-Mt line, 26H, phenyl ring, porphyrin term hydrogen,
-CONH-), 9.41 (-double line.

CMR spectrum (CDC13) δ (ppm) 26.
45 (-(JT3).

38.95, 3B, 84 (-C(CHs)s),
115.07 to 149.94 (phenyl term porphyrin term carbon), 175.39°175.51, 175.6
0 (-CONH-), 188.69 (-CHO)
.

(φ 2f(-PFP(CHO) 2.29 ,!i+
(2,20 mmol) K Dissolved in chloroform/methanol (5/1 (4/V)), NaBH4330m
9 (8,72 mmol) 'e After adding 10
Allowed to react for minutes. By purifying in exactly the same manner as in Example 4, 2-hydroxymethylbikeratophensporphyrin (2H-PF'P(CIj20H)) was obtained.

Yield 2.229C Yield 96.8) mp>3oo℃TT
, CRf =0.51) Chloroform/methanol (
10/1 (v/v) ) IR spectrum (KBr) 1690 (νC=01 amide).

1060 (C-OH) cm” and others, 1675 (ν
. -8゜Aldehyde) L-rn Vanishing visible spectrum (CHC/-3) λmax417,51
1°542 (shoulder absorption), 5B5,640nm FDMS spectrum rn/e 1040 (M±) elemental analysis (C6
5H68N805) Actual value (calculated value) H: 6.8
0 (6,58), C near 4.78 (74,97), 10
．． 65 (10,76) Chi PMR spectrum (CDC63) δ (ppm) −2,
62 (-double line, 211, pyrrole N-)I), 0.
036゜0.051.0.058,0.083 (each -
Heavy line.

36 H, -CH3), 2.79 (triple line, H
, -0H).

4.95 (double line, 2H, -CH20H), 7
．． 15-8.83 (multiplet, 26H, phenyl ring, porphyrin broken hydrogen, -CONH-'), 8.99
(- heavy line.

CMR spectrum (CDCf3) δ (ppm) 26.
42 (-CH3).

38.87 (four (Cf(3)3), 60.15 (
-CH20H).

114.02-148.20 (phenyl i summer, I5 ruphyrin ring carbon), 175.51.175.77.17
5.90 (-CONH-).

(V) 2H-PFP (CH20H) 104m! i
'(0.10mmol) Total dichloromethane 20ml
and cooled to 0°C. Phosdane 1.0 mmol
f, after adding 0.23 ml of carbon tetrachloride solution containing 1
Allowed time to react. After returning the temperature to room temperature and reacting for an additional hour, the solvent and excess phosdan were all distilled off under reduced pressure and dried. Nyloxymethylbicket fence porphyrin (2I(-PPP(CH20COCt)
) was obtained quantitatively in the form of hydrochloride.

TLCRf = 0.68 (silical plate, benzene/ether/acetone (515/1 (v/v/
v) )・2H-PFP (CH20H) has Rf under the same conditions.
=0.4421- FDMS mle 1 102 CMri ([above (
2H-PFP obtained with ψ (CH20COC/!,) 11
0~(0,10mmol) kjiku OA/Meta 720
ml, 125 μm (1 mmol) of 1-(3-aminozorobyl)imidazole, 0.1 ml of triethylamine.
4ml (1mmol)k was added and reacted at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was washed with water, dried, and purified using a silica dull column (2 F x 20 α) using a chloroform/methanol (10/1 (v/v)) solvent.

Yield 75m9 (yield 59.5%) TLCRf=0.39 (Silica Dull Plate, Chloroform/Methanol (10/1 (v/v))) IR,
(Vector (KBr) 1720 ('C=.+urethane), 1690 (νc=o+amide) 11 others Visible spectrum (CHCts) λmax 418,512.544
(Shoulder absorption), 585,640 nm Elemental analysis (as C72H77N1106) Actual value (calculated value) H: 6.37 (6,51) C: 22-72.23 (72,52), N: 12.78 (12 ,9
2) Chi PMR spectrum (cncz3) δ (ppm) −2,
60 (-double line, 2H, virol N-H), 0.00
7.0.051.

0.075, 0.1.17 (respectively - heavy line + 36
H+ -CH5C2,03 (triple line, 2H, 0CO
NI(CH2C, H2C, H2).

3.19 (quadruple 1!, 2H, 0CONHCH2C
H2CH2).

409 (triple line, 2H, 0CONHCH2CH2C
Dan 2).

5.04 (Two pairs of wires, H, CI (20CONr(>,
5.73 (multiplet, 2H, CH20CONH)
, 7.03-8.83 (multi-ft[,3oH, phenyl ring, porphyrin ring, and imidazole ring water X, -
CONH-).

CMR spectrum (CDC23) δ (ppm) 26.
45(-CH3), 31.43,37.78+44
．． 21(Ctt2CH2CH2)+38.89 (-C
(CHs)3), 61.32 (CH20CO
NH).

114.37-151.22 (phenyl term, porphyrin term, and imidazole JJ carbon), 156.
37(-0CONH-), 175.46, 175
．． 72, 176.16 (-CONH-).

(0,032 mmol) k TfTFl 0 ml
FeBr2.4H is dissolved in a nitrogen stream under boiling point reflux.
2092,1m9 (0,32mmol) and pyridine 0
．． 026 ml (0.32 mmol) k was added. 2
．． After reacting at the same temperature for 5 hours, drying under reduced pressure and purifying with a silica gel column (2 crnφ x 20 crn) using chloroform/methanol (10/1 (v/v)) as the total solvent, the iron valence ion was purified as a counter ion. Bre? Complex Fe(ITI)・Rr"" in the introduced form - Yield 30■
(Yield 71.0%) TLCRf = 0.27 (Silica Dull Plate, Rio.

Form/methanol (1,0/1 (v/v)) ) I
R Suiktor (KBr) 1.725 (C-o,
Urethane), 16! 10 (ν.-8, amide)
m-1 other visible spectrum (ct cz3) λmax 4
47, 505.

575.640,657 (shoulder absorption) nm elemental analysis (C
72H75N1j06F"lBr1) Actual measured value (calculated value) H: 5.60 (5,70), C: 64.80 (6
5,21), N: 11.38(11,62)ti Synthesis Example 2
゜(i) Cu(H)-PFP(CHO) 88 m?
(0.08 mmol) (mp 1.62-163℃
) 400 In9 (1,2 mmol) after total addition 20
Boil at reflux for an hour. After the reaction, the mixture was washed with a 10% aqueous citric acid solution, water, a 5% aqueous sodium carbonate solution, and water in this order, dried over magnesium sulfate, and then dried under reduced pressure. The residue was transferred to a silica gel column (2 (-rnφx 20 cm
) k to obtain cis- and trans-integrated Cu(1)-PFP (CH=CH-CO2CJ) k
Obtained.

(A) trans-Cu(IT)-PFP(CH=CH-
CO2CH3) yield 54.0 mIy (yield 58.4%)
TLCRf = 0.33 (silical plate, benzene/ether (415 (v/v))).

IR spectrum (KBr) 1725 (ν.-6, ester), 1690 (νC=Ol amide), 16252
5- Visible spectrum (CHCL3) λmax 422,542
゜5 8 1 nm FDMS spectrum n/e] 156 (M”,)
Elemental analysis (as C68H68N806Cu1) Actual value (calculated value) H: 5.78 (5,92), c near 0.
3 3 (70,60), N; 9.60 (9
,69) CH (B) cis-mouth starvation 1)-PFP(CH
=CH-CO2CH3) Yield: 9.3179 (Yield: 10
, 1ch) TLCRf = 0.47 (Silica
), hair ``en/ether (415 (v/v)
) ).

IR spectrum (KRr) 1720 (ν.-8, ester), 1690 (νC=Ol amide), 1630 acceptable spectrum (CHC/!, 3) λmax 416,
538.

574 nm FDrvs spectrum rQ/e 1156 (M±) Elemental analysis (as C6BFT68NBO6Cu1) Actual value (calculated value) H: 5.85 (5,92), C; 70.
39 (70,60), N; 9.55 (9,69)%-2
6= (ii)) Lance-Cu (1)-PFP (CH
=CH-CO2CH3)54”Q (0,047mm
ol ) k T'HF 20 me was electrolyzed. 10
After adding 100 μm of palladium supported on Qi activated carbon and carrying out a catalytic reduction reaction under a hydrogen stream at normal temperature and normal pressure for 6 hours, the catalyst kF was removed, and then the solvent was distilled off under reduced pressure. The entire residue was purified with a silica gel column (2,8ry+φX 40 cm) using a benzene/needle (1/Hv/v) solvent, and the copper of 2-(2-methoxycarbonyl)ethylbicketfence I ruphyrin was purified. Divalent complex (Cu(II)-PFP((CH2)2CO2CH
3') ) was obtained.

Yield i35.5■ (Yield 65.6) 'l'Lc Rf =0.50 (Silica gel plate, benzene/ether (1/1 (v/v)))
IR spectrum (KBr) 1730 (ν.-8, ester), 1690 (ν.-8, amide) tx', etc., visible spectrum (CHCL3) λmax 415 +
538572 (shoulder absorption), 622 nm.

FDMS spectrum rr1101158 (foundation) elemental analysis (as C6BH7oNBO6Cu1) actual value (calculated value)) I: 5.89 (6,09), C; 70.20 (70
, 48), N: 9.44 (9,67) Chi (1 width C
u(TI)-PFP((CH2)2CO2CI(3)
2 3.2 ``9 (0.02 mmol) was dissolved in acetone and hydrolyzed in the presence of an aqueous sodium hydroxide solution according to a conventional method to form copper 2-cal, A valence complex (Cu(II)-PPP((CH2)2COOH)) was obtained.

Yield 16.7 m9 (yield 72.9%) TLCRf
= (1,2F+ (Silica Dull Plate, Chloroform/Methanol (20/1 (v/v))) IR
Spectrum (Kllr) 1710 (νc=o + carboxylic acid), 169Q (νC=OlCO2CH3', etc.
1730 (vc=o, ester)i-1 disappearance.

Visible spectrum (cxct5) λmax415,53
7°573 (shoulder absorption), 622 nm FDMS spectrum m/a 1143 (Mi) Elemental analysis (as C67H6BNBO6Cu1) Actual value (calculated value) H: 5.84 (5,99), C near 0.00 (7
0,29), N: 9.54(9,79)%cXACu(
1)-PFP((CH2)2C00H)151v(0,
0.05 ml (0.69 mmol) of thionyl chloride dissolved in 10 ml of dichloromethane
Added k. After boiling under reflux for 2 hours, the mixture was dried under reduced pressure. 6l-(5-aminopentyl)-2-methylimidazole dihydrochloride (mp 142-143°C; for example, E' , Tsuchida et al.

Bull, Chem, Soc, Jpn, , 5
5, 1890 (1982)) 3.
2-(0,013 mmol) k Dehydrochloric acid according to the usual method, triethylamine 0.01 ml (0,072 ml)
It was dissolved in 5 ml of dichloromethane containing 'r. This was added dropwise to the above solution and reacted at 0 to 5°C for 1 hour, then returned to room temperature and left overnight.

After washing twice with the same amount of water, it was dried and concentrated under reduced pressure.

The residue was dissolved in chloroform/methanol (10/1 (v/v)
) Silica gel column using solvent (2ctnφX20I
:tn)), Cu (1299- yield 12.0 m9 (70.8%) TLCRf=0.27 (silica dull plate, chloroform/methanol (10/1 (v/v) )) IR spectrum (KBr) 1690.1665 (C-01 amide) Nishi-1 et al., 1710 (νC=01 carboxylic acid) (
I'm gone.

Visible spectrum (CHCL3) λmax415*5
37 +572 (shoulder absorption), 620 nm Elemental analysis (as C76HI33N1105Cu1) Actual value (calculated value) H: 6.21 (6,46), C near 0.
28 (70,54), N: 11.69 (11,90)%
1v (0,007mmol)'ft: Synthesis example 1 (1
After decopper removal and ionization in exactly the same manner as shown in Section 3, iron ions were introduced according to Synthesis Example 1 (vii), yielding exactly the same 30-ffi 7.1 m9 (yield 74.2%) TLCR.
f = 0.24 (silica gel plate, chloroborum/methanol (10/1 (v/v))) ■R spectrum (KBr) 1690 * 1665 ('
C=Ol amide) m-1 and others.

Visible vector (CHCL3) λmax 416,508
゜576.640.674 (, shoulder absorption) ('m'.

FDMS n1/e 1285 ((M+1) ±) Elemental analysis (as C76H83N1105Fe1Br1) Actual value (calculated value) H: 5.97 (6,12), C:
66.54 (66,81), N: 11.02 (11,2
Examples are shown below.

Example 1㎜9 was dissolved in 10 ml of benzene, and 2 m9 of 10% Nocladium supported on activated carbon was added thereto. After catalytic reduction under a hydrogen stream for 10 minutes, the above catalyst was all separated under a hydrogen stream to obtain an iron valence complex solution. The Q-band spectrum in this case was λmax 539 nm (curve a in Figure 1). Oxygen gas (1 atm) was added to the resulting solution at room temperature for 3
By blowing for 0 seconds, the spacer λmaxU54
4 nm (curve b in Figure 1). Next, by introducing nitrogen gas (1 atm) for 2 minutes, λmax was completely returned to its original position. Next, it was left in contact with the atmosphere, and spectra were measured every 10 minutes (Fig. 1, curve b).
”= c) However, in a state where all oxygen is adsorbed (oxygen complex)
Its half life was 5 hours.

Under the same conditions, a complex of picket fence heme and N-methyl imiguzole (ratio of the two: 1:5) had a half-life of 3 hours.

An iron valence complex was prepared in the same manner as in Example 2, and then the entire oxygen complex was obtained by completely introducing oxygen gas. The Q-band spectra obtained for each are the spectral changes of the complex consisting of picket fence heme and 1,2-dimethylimidazole in benzene (25°C) @
(J, P. Co11rnan et al., J.

Am, Chem, Soc, , 97, 1427
(1975), cf.), and reversible and repeated changes in the spectrum (Table 1) were observed as nitrogen and oxygen were blown.

Table 1 λmax (nm) Reduced type oxygen complex example 3゜m? (5,2X 10'rnol) and egg yolk phosphatidylcholine 76m9 (0,104 mmol) in chloroform/methanol (9/i (v/v))
The entire solution was dried under reduced pressure in a round-bottomed flask to form a thin film on the vessel wall, and then 0.05M-IJ acid buffer (pH 7,4
) (lti was added and shaken to obtain an emulsion solution. After sonication with ultrasonic stirring for 33 to 30 minutes in an ice water bath under a nitrogen atmosphere, 1 m of NADP was added.
9 glucose-6-phosphorus H8mq, ferredoxin 0,
02 m9, ferredoxin-NADP reductase Q
, l Tn9 and catalase 0.05 m! 7 was dissolved in 1 ml of the buffer used previously and added. After introducing nitrogen gas for a total of 2 minutes, 0.06 m9 of glucose-6-phosphate dehydrodenase was added to the mixture, and the mixture was reacted overnight at room temperature with a closed stopper to obtain an iron value complex solution.

The Q-band spectrum in this case is λmax538, 563
nm (Figure 2, curve a). By blowing oxygen gas (1 atm) into the resulting solution at room temperature for a total of 30 seconds, the wave torque λmax immediately shifted to 544 nm (curve b in Figure 2). Next, by introducing nitrogen gas (1 atmosphere) for a total of 2 minutes, λmax returned to its original position, confirming that oxygen was completely reversibly adsorbed and desorbed.

Example 3 was used except that Example 4 was used. An aqueous solution of an iron number 34 complex was prepared under exactly the same conditions as described above, and then oxygen gas was introduced to obtain the entire oxygen complex. The spectral changes obtained in response to each of these are based on the spectral change behavior of a complex made of picket fence heme and 1-lauryl-2-methylimidazole (molar ratio of the two: 1:50) prepared under similar conditions. (
E.

Hasagawa et al., Blochem, Bloph
ys, Res+Commun, .

105.1416 (1982)), and corresponding spectral changes (Table 2) were observed with similar reversibility upon repeated blowing of nitrogen, nitrogen, and oxygen. λmax (nm) Example 5.6 Example 3 and 4 except that 10m9 of cholesterol was added
After preparing the entire iron valence complex solution in exactly the same manner as described above, by introducing oxygen and nitrogen, the reversible change in the squictor shown in Table 3 was continuously observed.

Table 3 λmax (nm)

[Brief explanation of drawings]

FIG. 1 shows tenoFe(Ir)-PFP (CH20) in benzene FI solution prepared in Example 1 according to the present invention.
A spectral diagram showing reversible changes in the CONH(CH2)3N N complex due to oxygen and nitrogen blowing, and changes over time due to contact with air. Fig. 3 is a spectral diagram of the oxidation of the above complex embedded in phosphatidylcholine liposomes due to oxygen injection. Figure 1: Liquid receiver Figure 2: Ninaga

Claims (1)

[Claims] (1) General formula [where M is an iron (It) ion, R is a formula (where m
is 1 or 2, n is an integer from 3 to 5, X is 1000N
H- or -CONH-1 R1, R2 and R5 are each independently a hydrogen atom or an imidazole derivative group represented by a methyl group] 2-substituted metal-5,10,1
5,20-tetra [α1α, α. An oxygen adsorption/desorption agent containing an α-(0-piparamidophenyl)porphyrin complex as an active ingredient.