JPH01501063A - Purpurin, chlorin, and purpurin- and chlorin-containing compositions - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Purpurin, chlorin, and purpurin.

and the manufacture and use of chlorin-containing compositions Background of the invention field of invention The present invention relates to purpurin group, chlorin (cbrorin). production and use of metal complexes of purpurins and chlorins; The present invention relates to phosphorus- and chlorin-containing compositions. Purpurin is fused to a reduced pyrrole ring. The unsaturated allocyclic ring in purpurin is combined with the saturated ring in chlorin. Corresponding. Chlorin is useful as a green dye. Chlorin and purpurin are 1IfIj and administer them systemically, e.g. intravenously. , after administration they localize preferentially in tumors. Administer them into the tumor After localization, their presence is detected by irradiation with ultraviolet light that causes them to fluoresce. The chlorin and purpurin of the present invention can also be used in the treatment of tumors. After their administration and localization, irradiation with light at a wavelength that exhibits an absorbance peak can be performed. , producing a reaction that damages or destroys the localized tumor. purpurin and chlori The compositions containing these compounds have their solubility in organic liquids that are physiologically acceptable for intravenous administration. liquids and their suspensions in saline solutions.

Conventional technology The present invention relates to four types of proteins of the group having an unsaturated isocyclic ring fused to a reduced pyrrole ring. Luplin's prior art, Woodward et al.'s guide to editors. Journal of the American Chemical Society (JAC3) ), vol. 82, p. 3800 et seq., 1960 (Intermediate in the synthesis of chlorophyll ), as well as Witte et al. Me Infunasiral Edition (Ange@, Chew, Inte rnat.

Edit, ), Volume 14, No. 5, pp. 361 et seq., 1975 and Arnold (A. rnold) and others, Digital Op the Chemical Society, Parki transaxilane (Journal of the Chemical 5 ociety, Perkin Transaction) Is 1660 It is known as reported in a journal article by, et al., 1979. To purpurin Witte et al. or Arnold et al. Furthermore, European Patent No. 111 EP 142.732 is not suggested by others. We have disclosed certain chlorins in the group of It is said to disclose that it preferentially accumulates in cells (Chemical Abstracts). (C, A, ) 103:1232713).

Purpurins and chlorins structurally resemble porphyrins.

One type of porphyrin, called protoporphyrin, can be isolated from blood. can. Hematoporphyrin can be produced from protoporphyrin ■; Hematoporphyrin derivatives, often abbreviated as rHpDJ A chemical mixture derived from rufilin is administered intravenously to detect and treat tumors. It can be used as previously described for therapy. However, the accuracy of HPD Its composition is unknown; in fact, it is composed of many different porphyrins and related A mixture of compounds [for example, “Porphyrin Ph” otosensitization) J % David Cassel Kassel and Thomas J., Doughherty) W. Plenum Press, New York and Lo In conclusion, the chlorin of the present invention and purpurin are better suited for this use than HpD because they are single compounds. Preferably, the chlorin and purpurin exhibit absorbance bias at long wavelengths. , exhibits higher absorbance than HpD, and the long-wavelength peak indicates that long-wavelength light is concentrated on the tissue. It is advantageous because it can penetrate layers, and high absorbance is necessary to cause a certain degree of reaction. This is desirable because the light energy is small.

Brief description of the drawing Figure 1 shows the composition of the group of purines according to the invention in which an unsaturated homocyclic ring is fused to a reduced pyrrole ring. Structural formula for the genus complex.

Figure 2 shows the structure according to the present invention in which the allocyclic ring corresponding to the unsaturated allocyclic ring of purpurin is saturated. Structural formula for metal complexes of the chlorin group.

Figure 3 shows the group of porphyrins that can be used in the production of purpurin according to the present invention. It is a structural formula.

FIG. 4 is a structural formula for a porphyrin metal complex having the formula of FIG.

FIG. 5 is a structural formula for a group of purpurins according to the present invention.

FIG. 6 is a structural formula for a group of chlorins according to the invention.

Detailed description of the invention In one aspect, the present invention provides a pulley having the structure of FIG. 1 or FIG. 5 of the accompanying drawings. or a solution of chlorin in an organic liquid having the structure shown in Figure 2 or Figure 6. Yes, M in the above structure is a metal, such as AH, A A', Ce, Co, Cr + Cu + D y + Er, Eu + Fe, Ga, Gd, Hf, H o, In, La, Lu, Mn, Mo.

Nd, Ni, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm.

Sn, Tb, Th, Tt, TI, Ts, U, V, Y, Yb, Zn or Zr can be, Each of R1-R13 is H or CHO.

primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having the formula RJ(R*)z (where R1 is a carbon-to-carbon bond 1 to 4 carbons in which the bond is a single or double bond and at most one is a double bond is a divalent aliphatic hydrocarbon group containing atoms, and R5 is hydrogen or 1 to 2 carbon atoms. an alkyl group having children, the two R5 groups can be the same or different ), a group having the formula, RzN(R-)z" (wherein R1 is a group in which the carbon-to-carbon bond is a single 1 to 4 carbon bonds, at most one is a double bond, and at most one is a double bond is a divalent aliphatic hydrocarbon group having 1 to 2 carbon atoms; R4 is an alkyl group having 1 to 2 carbon atoms; a group in which three R, l can be the same or different), Formula, R, OR (in the formula, R2 is a carbon-to-carbon bond that is a single bond or a double bond and divalent aliphatic hydrocarbon radicals having 1 to 4 carbon atoms, at least one of which is a double bond ), or COJ', CHzCOJ' or CHgC HzCOzR' (wherein R' is H or a primary group containing 1 to 4 carbon atoms) or a secondary alkyl group, and R1 is such that the valences of the groups are both on the same carbon atom. , and 2 to 4 carbons feeding the carbon atom of purpurin, chlorin or metal complex It can be a divalent aliphatic hydrocarbon group having atoms.

Organic liquids are purpurin soluble and physiologically acceptable for intravenous and topical administration. It is something that will be done.

In another aspect, the present invention has the structure of FIG. 2 or 6 of the accompanying drawings, and R1 -R13# and M are chlorin having the above meanings.

Furthermore, in another aspect, the present invention has the structure shown in FIG. 1 or FIG. 5 of the accompanying drawings, and R 1-R13 and M have the above meanings, but R' is hydrogen or 2 to 4 is a group of purpurins, which are primary or secondary alkyl groups having carbon atoms of .

In yet another aspect, the present invention provides for administering an effective amount of purpurin or chlorin to humans or is administered to an animal patient and the relevant area of the animal is exposed to purpurin or chlorin at its absorbance peak. detecting and treating tumors, including irradiation with ultraviolet or visible light at wavelengths that have It is a method of treatment. Purpurin has the structure shown in Figure 1 or Figure 5 of the attached drawings, Chlorin has the structure shown in FIG. 2 or 6, in which M is a metal, Each of R1-R13 is H or CHOl primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having the formula RtN(Rs)x, where R1 is carbon to carbon 1 to 4 carbons in which the bonds are single or double bonds, and at most one is a double bond is a divalent aliphatic hydrocarbon group having elementary atoms, R2 is hydrogen or 1 to 2 carbon atoms is an alkyl group having an atom, and the two R5 groups can be the same or different. a group having the formula, RgN(R-)z" (wherein R2 is a carbon-to-carbon bond 1 to 4 carbon atoms with single or double bonds, at most one double bond is a divalent aliphatic hydrocarbon group having 1 to 2 carbon atoms, and R4 is an alkali group having 1 to 2 carbon atoms. a group in which the three R4 groups can be the same or different), Formula, RIOH (wherein R1 is a carbon-to-carbon bond that is a single bond or a double bond and divalent aliphatic hydrocarbon radicals having 1 to 4 carbon atoms, at least one of which is a double bond ), or COJ', CHzCOxR' or CI (t cHtco□R' (wherein R' is H or a primary group having 1 to 4 carbon atoms) class or secondary alkyl group, and R1 is a group whose valences are both the same carbon atom. and 2 to 4 carbon atoms bonded to purpurin, chlorin or metal complex. can be a divalent aliphatic hydrocarbon group having carbon atoms.

Purpose of invention Therefore, the object of the present invention is to provide a purpurine having the structure shown in FIG. 1 or FIG. 5 of the accompanying drawings. or a solution of chlorin in an organic liquid having the structure of Figure 2 or Figure 6. An object of the present invention is to provide a new composition.

Furthermore, the object of the present invention is to provide a purpurine having the structure shown in FIG. 1 or 5 of the accompanying drawings. or an aqueous solution of a chlorin having the structure of FIG. 2 or FIG. 6 in an organic liquid. It is to provide an emulsion.

Another object is to provide a group of proprines having the structure of Figures 1 or 5 of the accompanying drawings. It is to be.

Another purpose is to provide a group of chlorins having the structure shown in Figure 2 or Figure 6 of the accompanying drawings. It is to provide.

Yet another object of the invention is to provide one of said purpurins or chlorins to humans or animals. It is an object of the present invention to provide a method of detecting and treating tumors, which includes administering to a patient .

Description of preferred embodiments Examples 1-8 show that the present invention is directed to proprine and chlorin and their production. The present invention represents the best mode currently intended by the inventors. Directed to solutions of phosphorus and chlorin in organic liquids and the production of such solutions. The present invention describes the best form possible, and the in vitro and in vivo test methods! I! ulcer The best possible use of purpurins and chlorins for the detection and treatment of Describe the good form.

The term "percent V/VJ" in the examples and elsewhere refers to volume percent. and the term "percent W/W" means percent by weight; The term "group" is used in its ordinary sense and refers to -valent, saturated, aliphatic hydrocarbon groups. meaning, and the term "fulkylene group" is used in its ordinary sense, meaning one carbon pair A monovalent, aliphatic hydrocarbon that has a carbon double bond and the other carbon-to-carbon bonds are single bonds. all temperatures are in °C and the following abbreviations have the meanings shown below. g-milligram or milligrams, g-gram or grams, kg-ki kilogram or kilograms, milliliter or milliliters, Low centimeter or centimeters, t ≥ molar extinction coefficient, -1 milliwatt and nm = nanometer or nanometers.

Example 1 Novel pull according to the invention from nickel meso-formyl octaethylporphyrin The preparation of filin (hereinafter "purpurin NT2J") is described in this example. Kelmeso-formyl octaethylporphyrin is manufactured by Grigg et al. or Journal of the Chemical Society, Perkin Transa. Kushinzu (J, Chew, Soc, Perkin Trans,) I-, 1972, 1789, 1798, in a journal article by R1-R 8 is ethyl, R is C)(O, and M is Ni) the formula in Figure 4 of the accompanying drawings has. Two intermediates, R1-R8 are ethyl and R is Cl” CHCO zellzCHs and M is Ni, having the formula of Figure 4 of the accompanying drawings. lumeso-(β-ethoxycarbonylvinyl)octaethylporphyrin and R 1-In the attached drawings where R8 is ethyl and R is CH=CHCChCHtCH* Meso-(β-ethoxycarbonylvinyl)octaethylpolymer having the formula shown in Figure 3 Filin, was prepared during the procedure of Example 1. Purpurin NT2 has R1-R8 is ethyl, R9 is C0zCHzCHs, and RIO-R13 is hydrogen It has the formula shown in FIG. 5 of the accompanying drawings.

Nickel meso(β-ethoxycarbonylvinyl)octaethylporphyrin Notice Nickel mesoformyl occuethylborifylline 506mg and (carbeto Xymethylene ) triphenylphosphorane 1.024 g of xylene 50-! The melt inside The solution was heated under reflux for 18 hours. Cool the solution and remove the xylene under reduced pressure to remove the remaining The solid was dissolved in a minimum amount of dichloromethane and chromatographed on silica. It was.

A small fraction of nickel octaethylporphyrin and a major red fraction were collected. solvent was removed from the red fraction and the remaining solid was dissolved in equal parts dichloromethane and methanol. Recrystallization from a solvent consisting of alcohol gave 455 mg of small brown needles. product is nickel meso(3-ethoxycarbonylvinyl)octae by nuclear magnetic resonance. Identified as tilporphyrin, it is 405.530 and 565 nanometers visible spectrum absorbance peak ($94180.18604.27790) showed that.

Meso-(β-ethoxycarbonylvinyl)octaethylporphine 1 Nickel meso-(β-ethoxycarbonylvinyl)octaethylporphyrin 6 21 mg was dissolved in ti (96.7% W/W) sulfuric acid L QsJ. The solution was left at room temperature of about 22° for 2 hours, and dichloromethane Add 100 ml of water and then add saturated aqueous sodium bicarbonate to neutralize the sulfuric acid. did. The organic layer was collected, washed and dried; then the solvent was evaporated. residual coarse The product was recrystallized from a solvent consisting of equal parts dichloromethane and methanol. 552 mg of frenulum reddish-brown crystals were obtained, which was determined by nuclear magnetic resonance as a men-(β- It was identified as ethoxycarbonylvinyl)octaethylporphyrin. this The production of porphyrins is described in a journal article by Fuhrhop et al. Annalen del Hemi (Ann, Chew), 1976.1539~ It is disclosed on page 1559.

Purup1nNT2's Sting Men-(β-ethoxycarbonylvinyl)octaethylporphyrin 100+* A solution of 20 g of glacial acetic acid was heated under reflux for 24 h in a nitrogen atmosphere. Cool the solution at , remove the acetic acid under reduced pressure and dissolve the remaining product in a minimum amount of dichloromethane. Dissolved and chromatographed on silica to obtain a predominant green fraction; The medium was removed. The remaining solid was dissolved in 50% V/V dichloromethane and methane. When recrystallized from the glass, purple microcrystals 68a+g were obtained, which were determined by nuclear magnetic resonance. Confirmed as Purpurin NT2, 433.453.503.530.568. 648 and 695 nanometer Cl 89509.89509.14571 , 12143.18908.10582.42673) in the visible spectrum It was observed that there was a peak.

Example 2 Zn Purpurin NT2 11″ Purpurin NT 2.20 mg dichloromethane 1 5aj and methanol 51 A solution was prepared by dissolving 100 mg of zinc acetate in a mixed solvent consisting of is added to the solution and the resulting mixture is The reaction mixture was refluxed for about 4 minutes until it showed that the temperature was 100%.The reaction mixture was then concentrated to 7 liters and Cooled to room temperature of 22°. The precipitated product was collected by filtration and dichloromethane When dissolved in a mixed solvent consisting of 5 ml and methanol and 2 ml and recrystallized, Zn 2.18 mg of Lupulin NT was obtained in microcrystalline form. Gold body, Zn purpuri In NT2, R1-R8 are ethyl, R9 is C0zCHzCHs, and RI A compound having the formula of FIG. 1 of the accompanying drawings in which O to R13 are hydrogen and M is Zn; The objects are 413.435.535.578.618 and 663 nanometers (t1 95270.21949B, 14052.18886.28588.86733 ) has a visible spectrum absorbance peak.

Example 3 ``Crow 1 NT 2) (2J Noritsu Announcement) Dissolve 21.100 g of Purpurin NT in 20 g of tetrahydrofuran. Prepare a solution by adding 2 drops of triethylamine and add 20 mg of Pa Radium charcoal was added and the resulting mixture was placed on an inclined machining machine maintaining a slight positive pressure of hydrogen. Hydrogenation was carried out for 5 hours at room temperature of about 22° in a Nifold hydrogenator. Parasiu used Muum charcoal is from palladium 10% w/w and charcoal 90% w/w Configured. Filter palladium on charcoal from the colorless reaction mixture, stirring the filtrate vigorously. The solution was exposed to air for approximately 2'/□ hours until the solution turned brown, then the solvent was removed under reduced pressure. and the residue was dissolved in a minimum amount of dichloromethane containing 1% methanol V/V. chromatographed on silica. Collect the main blue band, The solvent was removed and the crude product was dissolved in dichloromethane containing 1% methanol V/V. 5-l and recrystallized to obtain 72 mg of a brown prismatic product, which was Nuclear magnetic resonance revealed that chlorin NT2H2, R1-R8 are ethyl and R9 is C0 tCHzCH3 and has the formula shown in Figure 6 of the drawings where RIO to RI3 are hydrogen It was WE as a compound. Chlorin N72 H2 is 403 in the visible spectrum ．． 500.535.558.610 and 660 nanometers (ε11465 Absorbance at 0.23532.5662.4246.8493.39455) It was recognized that there was a peak. The chlorin NT2H2 zinc complex is as described in Example 2. produced by the method, it has 408.515.545.59 in the visible spectrum 0 and 633 nanometers (ε145474.9858.5377.1583 2.59444) was found to have an absorbance peak.

The nickel complex of chlorin N72H2 was also prepared by the method described in Example 2, but Manufactured using nickel acetate instead of zinc acetate. Chlorin NT2H2 Ni The Kel complex has 405.498.533.588 and 630 nanometers in the visible spectrum. Nometer (ε145779.11034.8693.19392.64146 ) was observed to have an absorbance peak.

The zinc and nickel complex has R1-R8 ethyl and R9 C0tCHzCH 3 and 6M having the formula shown in Figure 2 of the drawings where RIO to R13 are hydrogen is a zinc complex. Zn for the body and Ni for the nickel complex.

Example 4 Purpurin NT2 and Purpurin NTI Solution of 100a+g of octaethylporphyrin (nylvinyl) in 20ml of glacial acetic acid was heated under reflux in air for 24 hours. Leave the solution at room temperature of approximately 22° until cooled. The solvent was removed under reduced pressure and the residue was diluted with methanol (containing 1% v/v). To the minimum amount of dichloromethane? 8 and chromatographed on silica. No. Collect the first and second predominant green bands, remove the solvent from the first band and extract the crude product. , dissolved in 4 p.m. of dichloromethane containing 1 percent N''/V of methanol and recrystallized. Then, “Purpurin NT1j, R1 is =CHCL, and R2 to R8 are ethyl. , R9 is C0tCHzCH3, and RIO to R13 are hydrogen. 40 mg of a compound having the formula shown in Figure 5 was obtained. Purpurin NTI is nuclear magnetic resonance It was confirmed by 438.510.540.583. in the visible spectrum. 653 and 715 nanometers (ε104158.9540, 11130.1 It has an absorbance peak at a wavelength of 5540.9020.42629).

The solvent was also removed from the second green band and the crude product was converted into methanol with 1% V When dissolved in dichloromethane 4ta14 containing /V and recrystallized, Purpurin NT2 ．． 39 mg was obtained and confirmed by nuclear magnetic resonance.

Purpurin NTI is hydrogenated by a procedure similar to that described in Example 3, resulting in the After post-treatment and chromatographic purification, chlorin NT2H2, 65 mog was gotten.

The procedure described in Example 1 was used to make other purpurins. List of starting materials used Typical intermediates and purpurins produced in Examples 5.6.7 and 8 are shown in Examples 5.6.7 and 8. Is displayed.

Example 5 Compound formula "Purpurin ET2J Figure 5.

*R1, R3, R5 and R7 are CM, and R2, R4, R6 and R8 are CHtCH3.

In the starting materials, R is CHO and M is Ni.

In the first intermediate, R is Cl=CHC01CHxCHs and M is Ni.

In the second intermediate, R is Ctl-CHCOzCHzCHx.

In Purpurin ET2, R9 is COICH, CH2, and RIO to R13 are hydrogen It is.

Nickel meso-formyl ethioporphyrin I is manufactured by Johns Journal article by On) et al., Journal of the Chemical Society I - (J, Chell, Soc,) (C) 1966. Disclosed on page 794 It is.

Example 6 Compound formula [Purpurin JPIJ Fig. 5°1 Manufactured as shown in the car postscript *Umbrellas H1, R3, R5 and R7 are CB, = R2, R4, R6 and R8 is CHtCHxC (hclh).

In the starting materials, R is CHO and M is Ni.

In the first intermediate, R is CH-CHCOzCHtCHx and M is Ni.

In the second intermediate, R is CH=ClIC0□CR2C)IS.

In Purpurin JPI, R9 is CO□co, cH, and RIO to R13 are hydrogen. It is.

Nickel mesoformyl coproborphyrin I tetrame used in the procedure of Example 6 The thyl ester starting material was the commercially available cobroporphyrin I tetramethyl ester. (formula shown in Figure 3 of the attached drawings) and then nickel cobrovolufirin ! In both cases, tetramethyl ester was produced (the formula in Figure 4 where M is Zn). where R1, R3, R5 and R7 are CH, and R2, R4, R6 and R 8 is COx (JIzCO□CH,

Ni coproporphyrin I tetramethyl ester is cobroporphyrin ■ tet La methyl ester 100+IIg of dichloromethane 5011I! and methanol Le51Ij! Produced from a solution in a mixed solvent consisting of and 100 mg of nickel acetate did. The mixture prepared by adding nickel acetate to the solution was The reaction mixture was then refluxed for approximately 42 hours until the chelation indicated that the chelation was complete. The material was concentrated to 7I11 and allowed to cool to room temperature of about 22°. Filter the precipitated product , and converted into a mixed solvent consisting of dichloromethane 5-p and methanol 2-1. When dissolved and recrystallized, 98-g of Ni cobrovolphyrin I tetramethyl ester was gotten. The compound has 392.515 and 552 nanometers in the visible spectrum. It shows absorbance peaks at , 19.1 and 2.56.

Nickel mesoformyl volphyrin I tetramethyl ester is the following substance Prepared from: freshly distilled phosphorus oxychloride 2.8@1, dried dimethyl chloride Lumamide 2. z, nickel-cobroporphyrin I tetramethyl ester 10 0 mg dry 1,2-dichloromethane 75-1 and saturated aqueous sodium acetate 7 Cool the solution in dimethylformamide on a water bath and remove the phosphorus oxychloride from it. Soaked in soy sauce. The resulting solution was left at room temperature for 30 min, then warmed to 50 °C. Next, add the nickel knob porphyrin tetramethyl ester solution while stirring. 0 reaction mixture added dropwise to the phosphorus oxychloride solution and the addition was carried out over a period of 30 minutes. was maintained under agitation at approximately 50° for another 2 hours, during which time the color changed from red to green. When a change to 0 was observed, a sodium acetate solution was then added to the reaction mixture, and the This was continued for an additional 2 hours.The organic and aqueous phases were then separated and the aqueous phase was dissolved in dichloromethane. The organic phase and dichloromethane extract were then combined and evaporated to dryness. . The remaining solid was dissolved in a solvent consisting of equal parts dichloromethane and methanol. When recrystallized, 86s+g of red microcrystals were obtained, which was identified by nuclear magnetic resonance as nickel. Identified as lumesoformyl cobroborphyrin I tetramethyl ester . The absorbance peaks are at 400.420.558 and 645 nanometers in the visible spectrum. Permitted with a relative strength of 10.10.8.69.1.02 and 1 respectively in meters It was done.

Example 7 Compound formula "Purpurin GG2J Figure 5.

*R1 to R8 are CH and C11.

In the starting materials, R is CHO and M is Ni.

In the first intermediate, R is CH”CHCOzCHsteal, M l!Ni theal .

In the second intermediate, R is CH"CHC (hCHste).

In purpurin GG2, R9 is CoICL and RIO-R13 is hydrogen.

Example 8 compound formula Starting material, Kobukuchi I Figure 3 1st intermediate, nickel knob ■ Figure 4 1 2nd intermediate, nickel metho (β-E) Toxy Figure 4 0 carbonyl vinyl) Cob mouth ■ Third intermediate, meso-(β-ethoxy tertiary P carbonyl) Kobukuchi 1 “Purpurin CCIJ Figure 5.

*R1, R3, R5 and R7 are CH3T: Yes, R2, R4, R6 and R 8 is CHtCHzCOzCHs T: Yes.

In the starting materials, R is CHO.

In the first intermediate, R is CHO and M is Ni.

In the second intermediate, R is CB=CHCOzCHzCHs, and M is Ni. Ru.

In the third intermediate, R is CH=CHCOzCHtCRs.

In Purupuri 7CCI, R9 is C (hcH3te), RIO to R13 are hydrogen .

Hydrogenate Purpurin ET2 and Purpurin JPI using the procedure of Example 3 chlorin ET2H2 and chlorin ET2H2 in which the isocyclic ring (to which the R9 substituent is attached) is saturated. and chlorin JPIH2 were produced. Chlorin has the same substitution as the starting purpurin group, but had the structure of FIG. 6 instead of the structure of FIG.

The procedure of Example 4 was used to prepare other zinc and nickel complexes.

Purpurin and chlorin starting materials, zinc or nickel compounds used and The complex is shown below: starting purpurin zinc or nickel -fi 虱哄り” 1 A magazine fl student Purpurin ET2 Zinc acetate Zn Purpurin E-cho 2 if Nifkel Ni Purpurin CG2 Zinc acetate 2n Purpurin GG2 Nickel acetate Ni Chlorin ET2H2 Zinc acetate Zn Chlorin ET2H2 Nickel acetate Ni Chlorin NT2FI2 Acetic acid 1!　 Ag Purpurin NTI Zinc Acetate Zn Purpurin JPI Zinc acetate Zn Chlorin Ni2O3 Tin chloride (2) Sn Purpurin ET2 Tin chloride (2) Sn-Xuan-Δ1’, nm (・) Purpurin ET2 406 (16, 69), 424 (15, 26), 502 (1 , 36).

531(1), 566(1,5), 695(3,47) Chlorin ET2112 400 (70,16), 498 (5,53), 530 (1,29).

555(1), 606(1,91), 662(20,82) Zn chlorin ET2 H2401 (20, 36), 530 (1), 56B (1, 18).

630 (3,20) Purpurin ET2 434 (16,44), 530 (1), 576 (1,31) .

612 (1,77), 660 (5,0) Ni Purpurin ET2 434 (5,1 4), 657 (1) Ni microrind 2N2 404 (11,70), 497 (1), 622 (4, 41 > Purpurin JP1 409 (22, 41), 504 (1,67), 54N1.21).

567(1,08), 647(1), 6903.79) Chlorin JPI) 12 401 (14,53), 650 (1) Purpurin GG2 406 (22,94> , 427(19,18), 500(1).

526(1), 565(1,89), 637(0,76).

695 (5,25) Zn purpurin cc2 436(8,33), 616(1), 66N3.43) Ni pullpurin CG2 427(4,20), 648(1) Pull according to the present invention In vitro and in vivo studies of purines and chlorins were also performed. in vitro test For testing, the compound was added to dimethyl sulfoxide or by the trade name Protosorb (PRO). TO5OLV) and 0.0% in phosphate buffered saline. Diluted to a concentration of 10 mg/wll. The test is FAXFT (N-(4-(5- Nitro-2-furyl)2-thiazolyl]formaldehyde) induced runt bladder 11 It was performed on XI cells. Two tests were performed, uptake and toxicity. 7) Bladder tumor cells were induced by FANFT at 0.0101g/yal at 4°C. 'Incubate for 1 hour at 37° with a solution of lubulin or chlorin. the incubation medium was removed and the cells were washed with phosphate-buffered saline. Wash three times and extract and quantify purpurin or chlorin retained by the cells. It included: The procedure used to study the use of HpD in rat tumor cells was Miscellaneous gt gf5 sentences by Garbo et al., Analytical Biochemistry Mistry (Analytical Biochemistry), Volume 151 (No. 1), pp. 70-81, 1985.

Toxicity testing includes the incubation and washing steps of the uptake test followed by 590 na Primary cell survival involving irradiation of cells with red light of wavelengths greater than nanometers Eliminate trypan blue, and miscellaneous f by Schneso') (Schneck+R,) k F sentence, Archives of Pathology and Laboratory Medicine (Arch, Path, (Leb.

Med, )) 35.857 page, 1943. Ta.

Uptake tests were positive for purpurin NT2 and chlorin NT2H2 . Toxicity test results were determined using HpD, phosphate buffered saline, and purpurin or cream. The following table shows the toxicity test results for the solvent system in which Lorin was dissolved.

Trial, r゛゛　-”L-holding power J! Nono L-purpurin NT2 46 Chlorin NT2H251 HpD 42 Phosphate buffer 93 Mixed solvent 96 In vivo testing was performed using implantable FANFT (N-[4-5-nitro-2-)lJru)- Males weighing 135-150 g implanted with 2-thiazolyl]formamide) tumor system. The experiments were carried out on a Fischer 344 raft. , S, H,) and others, Cancer Research ), pp. 1924-1927, 1984-5]. 2 tumors was implanted into the subcutaneous tissue of the abdominal wall of each test animal, and each tumor had a diameter of approximately 1 It was 0.

The purpurins and chlorins tested were treated with commercially available nonionic solubilizers and ethylene. Reacting oxide and castor oil at a ratio of 35 moles of ethylene oxide per mole of castor oil. 1,2-propanediodine is dissolved in the emulsifier obtained by solution and 0.9 vasene) w/w sodium chloride An emulsion was formed with an aqueous solution. The specific nonionic solubilizing agent used was named Cremophor. (CREMOPHOR) available from BASF under E.L. Recall, glycerin polyglycol, polyethylene glycol and ethoxy Composed of fatty acid esters of glycerin.

The test solution contained 50 tg of purpurin or chlorin, warm solubilizer 1 or 2111 ( (sufficient to dissolve the test compound), a mixture containing 32.9% w/w solubilizer Enough to make a solution of purpurin or chlorin in the diol/soluble agent solvent. 1. Prepared from 2-propanediol and finally tested? To make 8 liquid 10n+A Add enough 0.9% w/w aqueous sodium chloride to remove the pulp in the test solution. The lowest degree of phosphorus or chlorin was 5 mg/mA. Each test solution Dissolve the purpurin or chlorin in the solubilizer under mechanical shaking and stirring; Dilute the resulting solution with the indicated amount of 1,2-propanediol and add sodium chloride to the diluted solution. prepared by adding lium solution. paired for use with each test solution. A coloring solution was also prepared. except that controls do not contain purpurin or chlorin. It was the same as the test solution. The test solution was prepared in air, but did not react with oxygen. A nitrogen atmosphere appears to be advantageous because the chance of oxidation is minimized.

The test involved injecting each rat with the solution of purpurin or chlorin under test, at a dose of 4 mg. Lupurin or Chlorin per kg body weight or 10ml/g Purpurin or Chlorin One of the two tumors was injected with one body weight of phosphorus or an equivalent volume of the appropriate control. Irradiate the animal with light for 0 minutes and dissect the animal! This includes checking for ulcers. The injection is done on the back It was done through the tail vein. One irradiation of the tumor was done 24 hours after injection in each rat. The other of the two tumors was shielded by an opaque box.

Tumor temperature and body core temperature were measured using a thermistor placed into the tumor and into the rectum. It was monitored using the Tumor temperature is determined by directing a jet of cooling air onto the tumor. Body core temperature was maintained within 2″ by adjusting the body temperature.

The light source is Corning Glass Works. 500 watts with red filter available under the designation 2418 from It was a slide floodlight with a bulb. The light is reflected 90" by a silver-plated mirror, It was focused onto the tumor with a secondary focusing lens. The light intensity on the tumor is determined by United Detection United Detector Technology ) available under the designation rUDT #351J from was monitored and maintained at every 200 mw.

Six rats were injected with purpurin or chlorin test solution and two rats were given appropriate controls. solution was injected.

Four hours after irradiation, three of the rats injected with the test SA solution and paired were necropsied. . 24 hours after irradiation, three other rats injected with the test solution and another control A similar autopsy was performed on the infected animals. During the study, rats were given barbiturate anesthesia (65 mg every It was under the weight of dazzling.

The tumor was then embedded in paraffin and cut into 3 sections perpendicular to the long axis. Cut into 5 micron sections. Sections were stained with hematoxylin and eosin.

Histological examination of stained sections showed purpurin NT2, purpurin GG2 and purpurin. Bleeding and tumor cells were observed in specimens taken 4 hours after irradiation from animals injected with ET2. Roughly similar areas of cystic necrosis were shown. However, tumor cells that appear to be alive Admitted. Inject Purpurin NT2, Purpurin GG2 and Purpurin ET2. Tumor necrosis in specimens taken 24 hours after irradiation from irradiated animals was extensive and life-threatening. No existing tumor cells were found in these subjects.

No tumor changes were observed in specimens removed from animals injected with the control solution.

Tumor necrosis was observed in specimens removed from animals injected with purpurin NTI at 4 hours post-irradiation. Tumor necrosis was complete both after treatment and 24 hours after irradiation. However, the irradiation It was observed that some of the animals developed extensive liver damage. Liver damage is 715 nano The high absorbance peak of purpurin NTI in meters and the wavelength of such Twisting occurs due to the tissue's relative transparency to light. Purpuri remaining in the liver There was a large amount of NTI, which caused damage during irradiation. However, this is purpurin NTI This means that it is very effective when used appropriately.

The in vivo test procedure also includes purpurin NT2, purpurin GG2, purpurin N Chlorin NT2H2 and chlorin E instead of T1 and purpurin ET2 It was used to evaluate solutions using T2H2.

Set of stained sections from rats injected with chlorin NT2H2 and ET2H2 solutions Textile testing shows that these chlorins are essentially equal in this test, compared to purpurin NT2. , Purpurin GG2 and Purpurin ET2 (hereinafter, the only difference observed) The main reason for this is that chlorin was shown to cause less bleeding within tumors.

Purpurin JPI, Zinc Purpurin ET2, Tin Chlorin NT2H2, Tin Purpurin Purine ET2, silver chlorin NT2H2, zinc purpurin NTI and zinc purpurin All phosphorus JPIs were tested using the above-mentioned in-vivo test procedures. It was observed that tumor necrosis occurred. It was.

Some compounds can be tested according to the in vivo test procedure described above but at lower doses. I chose it. Zinc purpurin ET2 (ZnE D2), tin chlorin N72 H2 (SnN72H2), tin purpurin E T2 (SnBr2), plastic Lupurin ET2 (ET2) Purpurin NT2 (NT2) and Purpurin NT Some results of the NTI test are summarized in the following table: Test dose results Compound -g/kg ZnET2 0.25 Tumors in all test animals were irradiated 12 days after irradiation It was smaller than before.

5nNT2H20,25 80% of test animals were tumor-free 12 days after irradiation Ta.

5nE72 0.25 40% of test animals were tumor free 12 days after irradiation Ta.

ET2 1.0 50% of test animals were tumor free 12 days after irradiation.

NT2 1.0 Tumors in all test animals increased 12 days after irradiation than before irradiation. A small song.

NTI '1.0 20% of test animals treated the tumor with Purpurin NT 12 days after irradiation 2. Purpurin ET2, Purpurin JPI, Purpurin GG2 and Purpurin The preparation of CCI is described in Examples 1.5.6.7 and 8, respectively. Each In the case of purpurin, R1-R8 have a certain meaning and RIO-R13 are hydrogen. These purpurins have the structure shown in FIG. 5 of the accompanying drawings, and R1-R8 are It has the same meaning as lupulin, and R is C1l -CRCOgcHicHz or CH -CHCOzCHs was a porphyrin gold having the structure shown in Figure 4 of the accompanying drawings. prepared from genus complexes. Due to the nature of OR in the porphyrin starting material, the purpuri in which R9 was C(hcHtc)Is or co, co, R10-R1 In order to produce purpurin having the structure shown in Figure 5 of the attached drawings where 3 is hydrogen, Are other porphyrins required for substitution in luphyrin disclosed in the literature? Alternatively, it can be produced by methods disclosed in literature. In general, Porphyry by condensation of two viroles and then by condensation of two of the condensation products. manufactured by The two condensation products can be the same or different, each with the same It can be produced by condensation of one or two different pyrroles. R1-R 8 each H or CHO.

primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having the formula RzN(Ri)t, where R1 is carbon to carbon 1 to 4 carbon atoms in which is a single or double bond and at most one is a double bond a divalent aliphatic hydrocarbon group having children, R1 is hydrogen or 1 to 2 carbon atoms; and the two R1 groups can be the same or different) A group having the formula, RzN(Ra)s" (wherein R is a single carbon-to-carbon bond having 1 to 4 carbon atoms with at most one double bond is a divalent aliphatic hydrocarbon group, and R4 is an alkyl group having 1 to 2 carbon atoms. a group in which the three R4 groups can be the same or different), Formula, RIOR (wherein R1 is a carbon-to-carbon bond that is a single bond or a double bond and divalent aliphatic hydrocarbon radicals having 1 to 4 carbon atoms, at least one of which is a double bond or C0tR', CBzCO□R' or C)Iz CH*C(hR' (wherein R' is H or a primary group having 1 to 4 carbon atoms) or secondary alkyl group) The structure of Figure 3 of the accompanying drawings which is (without the alkoxycarbonylvinyl substituent R) All the birroles necessary for the production of porphyrins with 0 then alkoxycarbonyl vinyl group which can be produced by known methods It can be introduced by the known method disclosed in Example 1. These porphyrins are The structure of FIG. 5 of the accompanying drawings in which RIO to R13 are hydrogen when used in the procedure of Example 10 Produces purpurin with . Such purpurin is produced by Vilsmeier (Vil s*1er) to introduce a formyl group as RIO and R'13 by reacting with a reagent. or from which chlorin can be produced by the method of Example 3. Formyl group can be introduced as RIO in chlorin using Vilsmeier's reagent. can do. The formyl group is reduced to CH, if necessary after separation of isomers. or can be reduced to cnzoH or converted to an oxime group. and then convert it to a cyano group, which then converts it to an amide. be able to. Formyl groups can also be reacted with Winchch's reagent to form alkyl and alkylene groups. or carboxy side chain, or an amine or carboxy side chain at the RIO or R13 position. or the previously identified substituents can be introduced with an alcoholic OH function. . After introducing the desired groups as RIO1R13 or both, purpurin or A desired group can be introduced as R11 by reacting chlorin in the same manner.

Finally, chemistry can be used to introduce the desired group as R12.

The corresponding chlorin can be prepared from purpurin by the method described in Example 3. The corresponding purpurins can be prepared from chlorin by oxidation; metal Preparing the complex by the method of Example 2 or a variant thereof discussed below. Can be done. Using the method of Example 4, i.e., cyclization of porphyrins in air. Producing Other Purpurins Having R1 Groups Bonded to It by Carbon-to-Carbon Double Bonds In particular, using the method, R1 can be bonded to one carbon atom and to a carbon atom of a purpurin, chlorin or metal complex. Purpurin is a divalent aliphatic hydrocarbon group having 2 to 4 carbon atoms. can be done. However, hydrogen to convert these purpurins to chlorin The addition also saturates the R1 double bond. The hydroxyl group is introduced into the molecule and the reflux temperature Since the water component is eliminated at a certain temperature and a double bond is formed, the R1 double bond in Example 4 is It will be appreciated that the reaction between the hydroxyl groups and the hydrogen formed during the procedure occurs at low temperatures. can be prevented by cyclization with It can be hydrogenated to phosphorus and a double bond with R1 can be formed by heating. Wear. However, purpurin, which is attached to the R1 substituent by a double bond, is more easily synthesized. It will be appreciated that it is preferred over the corresponding lylorin because of its ease.

The purpurins and chlorins according to the invention in which RIO to R13 are hydrogen may be If the children are equal, the preparation of compounds with other groups at these positions is complicated and time consuming. R9 is CO, R' and R' is 1 to 4, which is preferable because it is expensive. The purpurins and purpurins according to the invention are primary or secondary alkyl groups having a carbon atom. and chlorin also indicate that, other factors being equal, these groups give rise to purpurin. These R The ester of the 9-substituted group can be reduced to the formyl group and reacted as previously discussed. R1-R8 or RIO to R13 substituents can be introduced.

The method of Example 2 can be used to produce other purpurins and various chlorin metal complexes. can be used. Specifically, equivalent amounts of other purpurins or chlorins are Can be used in place of Lupurin NT2, or copper acetate, nickel acetate, vinegar Using cobalt acid, silver acetate, palladium acetate or platinum acetate in place of zinc acetate or both substitutions can be made. In this way, M The purpurin metal complex having the formula shown in Figure 1, which is one of the metals listed in this section, is It can be produced from purpurin having the formula shown in the figure, where M has a similar meaning. A chlorin metal complex having the formula shown in Figure 2 is produced from chlorin having the formula shown in Figure 6. can be done. Other complexes were prepared by the method of Example 2 using cation-containing salts other than acetate. A trowel can be manufactured and has the structure of FIGS. 2 and 5, but M is simply gold. A metal complex is formed that does not represent a genus anion. Example 20 Substitution of Zinc Acetate in the Procedure Examples of salts that can be used are then identified along with the nature of M in Figures 2 and 5. .

-11-1 The nature of M FeCj! sFe(C1,) MnC1a Mn(Cf) lncfs In(Cf) V(f,”V(0) T f (CFsCOz) s T R (OAC) (Hf0) SnC11Sn (OH) z (Rh(CO)IC#)! Rh(C1)(H2O) *solvent instead of glacial acetic acid Use phenol as

The procedure of Example 2 also uses phenol instead of glacial acetic acid and pencil instead of zinc acetate. By using a metal chelate of tan-2,4-dione, it can be transformed into purpurin and and chlorin complexes can be produced. Metals that can react in this way (penta (2,4-dione chelate) and the nature of M in the resulting complexes are shown in the following table. Will be: The nature of metal M The nature of uM Aj! A 1 (acac)” Tn Th (acac) tSc S c (acac) U U (acac) zGa Ga (acac) La La (acac) zIn In (acac) Ce Ce (acac) M o Mo (acac) Nd Nd (acac) Ti Ti (acac) t Ss 5s (acac) Zr Zr (acac) 2 Gd Gd (ac ac) Hf Hf (acac) t Tb Tb (acac) Eu Eu (acac) Dy Dy (acac) Pr Pr (acac) Ho H o (acac) Yb Yb (acac) Er Er (acac) Y Y (acac) Tm T-(acac) Lu Lu(acac) * Pentane 2,4-dione part of the chelate with the metal.

The purpurin and chlorin complex was also prepared using the procedure of Example 2 instead of glacial acetic acid. using dimethylformamide instead and CrClI,z instead of zinc acetate. It can be manufactured using Formation of metal complexes using dimethylformamide occurs at higher temperatures due to its high boiling temperature. M in the complex is Cr (OB ).

Similarly, the purpurin and chlorin complex was prepared using glacial acetic acid according to the procedure of Example 2. Pyridine can be produced instead of pyridine, and pbc*z can be used instead of zinc acetate. Ru. M in the complex is pb.

Purpurin in specific nonionic solubilizers available under the name Cremophor EL Formation of solutions and processing of such solutions with 1,2-propanedione and salt solutions The manufacture of emulsions concerns the use of such solutions for the detection and treatment of Illulcers. As mentioned before. Purpurins, chlorins and their metal complexes are Emulsions that can be dissolved in nonionic solubilizers and whose solutions can be administered intravenously For example, ethylene oxide and castor Other reaction products with petroleum oils can be used as such, as well as ethylene, propylene and and other similar oxides with other fatty acids, as well as propylene and other The reaction product of the oxide of g (D and castor oil can also be used. Similarly, 1.2 - Use of glycols other than propanediol in the production of intravenous emulsions. or in particular to the solubilizing agent available under the name Talemofor EL. If a solubilizer is prepared that has a relatively lower viscosity and greater water compatibility, Recall can be omitted. Simply confirm that the solution or emulsion is physiologically acceptable. in a concentration suitable for intravenous or topical administration or can be diluted to a suitable concentration. It would be necessary and desirable to have an infinite number of such solutions. and emulsions will be clear to those skilled in the art from the above specific disclosure; 9 percent) h/w or any other concentration of sodium chloride; Saline solutions such as It can be used as long as it is physiologically acceptable for intravenous administration; in fact, other aqueous phases may be preferred later. In fact, other aqueous or organic phases may be preferred for topical administration. I can do it.

Doses ranging from 0.25 to 10+ag/kg body weight were used for the in vivo procedure. single Depending on the dose administered, the biological results reported may be the lowest or highest dose. It was confirmed that he was alive. Therefore, simply a book on tumor detection and treatment an effective amount of purpurin or chlorin according to the invention, preferably as small a dose as possible. that it is necessary to use the drug and that the exact dose can be determined by routine testing. Although systemic, especially intravenous, administration has been described, there are few It will also be appreciated that topical administration may be appropriate in some cases.

Irradiation of tumors containing purpurin, chlorin or metal complexes according to the present invention is performed as described above. The surface can be irradiated by an ordinary light source, or the surface can be illuminated by a laser. It can be irradiation. The irradiation can be carried out by inserting optical fibers into the body of the tumor, e.g. It can be via.

Various changes and modifications may be made to the specific details of the invention as defined in the claims. This can be done without departing from the spirit and scope.

FIG.2 FIG.3 FIG.5 FIG.6 Mr. Kunio Kogawa, Commissioner of the Patent Office 1. Patent application indication PCT/US 861028243, patent applicant Name: The University of Toledo 2 people outside of Toledo 4. Agent Address: 3-3-1 Marunouchi, Chiyoda-ku, Tokyo Telephone: (211) 8741 6. List of attached documents 1 translation of the written amendment amendment 8. As a novel composition, purpurin or the attached A purpurin metal complex having the structure shown in FIG. 1 of the drawings, in which: M is Ag, A1. Ce, Co, Cr, Cu, Dy, Er.

Eu, Fe, Ga, Gd, Hf　, Ho, In, La, Lu.

Mn, Mo, Nd, Ni, Pb, Pd, Pr, Pt, Rh.

Sb, Sc, S+*, Sn, Tb, Th, Ti, Tj! , T-.

U, V, Y, Yb, Zn or Zr, and each of R1-R13 is , primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having children whose valences are both on the same carbon atom, and having 1 to 4 carbon atoms bonded to a carbon atom of a purine, chlorin or metal complex. a divalent aliphatic hydrocarbon group, Formula RZN divalent aliphatic carbon having 1 to 4 carbon atoms and at most one double bond is a hydrogenated group, and R1 is hydrogen or an alkyl group having 1 to 2 carbon atoms. (the two R3 groups can be the same or different), a group having the formula RzN C Ra) s' (in the formula, R2 is a carbon-to-carbon bond that is a single bond or a double bond, and (A divalent aliphatic hydrocarbon group having 1 to 4 carbon bonds, one of which is a double bond) , R4 is an alkyl group having 1 to 2 carbon atoms, and three R4 groups are the same. radicals having the formula RzoHC (which can be one or different), where 32 is carbon 1 to 4, where the bond to carbon is a single bond or a double bond, and at most one is a double bond is a divalent aliphatic hydrocarbon group having 5 carbon atoms, or C0zR', CHzCOzR' or CHtCH2CChR' (wherein, R' is H or a primary or secondary alkyl group containing 2 to 4 carbon atoms ) and R1 is the only one in which the valences of the groups are both on the same carbon atom, and having 2 to 4 carbon atoms bonded to carbon atoms of phosphorus, chlorin or metal complexes purpurin or purpurin metal, which can be a divalent aliphatic hydrocarbon radical Complex.

international search report 1*+e+Suzuki 1mM1Ass&t#14MNo, PCT/US86102B2J 1st page continuation ■Int, C1,' Identification symbol Office serial number // A 61 B 10100 T-8119-4C[F]・Inventor Selman Steven A. Methito [Co., Ltd.] Inventor Climber Birnbaum Ma Ameser Rai ■Applicant: The Medical College, Amebu, Ohio C Applicant Saint Vincent Medi American Cal Center 4534 Granville Co., Toledo, Ohio 43615, United States Silica United States Ohio 43606) Ledo Burlington Dove 23 07 Silica United States Ohio 43699 Toledo Sinis Pio Ni Tux 10008 Silica United States Ohio 43608) Ledo Cherry Street 221 3

Claims (15)

[Claims] 1. Purpudding has the structure shown in Figure 5 of the attached drawings, and has the structure shown in Figure 1 of the attached drawings. a purpurin metal complex, a chlorin having the structure shown in Figure 6 of the accompanying drawings, or A metal complex of chlorin having the structure shown in Figure 2 of the attached drawings in a solvent containing an organic substance. a solution, in the structure, M is Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, G d, Hf, Ho, In, La, Lu, Mn, Mo, Nd, Ni, Pb, Pd, P r, Pt, Rb, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U , V, Y, Yb, Zn or Zr, and each of R1 to R13 is H or CHO, primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having children whose valences are both on the same carbon atom, and having 2 to 4 carbon atoms bonded to a carbon atom of a purine, chlorin or metal complex. a divalent aliphatic hydrocarbon group, Formula, R2N(R3)2 (wherein R2 is a carbon-to-carbon bond that is a single bond or a double bond) divalent aliphatic carbon having 1 to 4 carbon atoms and at most one double bond is a hydrogenated group, and R3 is hydrogen or an alkyl group having 1 to 2 carbon atoms. and the two R3 groups can be the same or different), the formula R2N (R4)3+ (wherein R2 is a carbon-to-carbon bond that is a single bond or a double bond, and divalent aliphatic hydrocarbon radicals having 1 to 4 carbon atoms, at least one of which is a double bond , R4 is an alkyl group having 1 to 2 carbon atoms, and three R4 groups are groups having the formula R2OH (which can be the same or different), in which R2 is Carbon-to-carbon bonds are single or double bonds, with at most one double bond 1 a divalent aliphatic hydrocarbon group having ~4 carbon atoms), or , CO2R', CH2CO2R' or CH2CH2CO2R' (where R' is H or is a primary or secondary alkyl group having 1 to 4 carbon atoms) and R1 is the only one in which the valences of the groups are both on the same carbon atom, and having 2 to 4 carbon atoms bonded to carbon atoms of phosphorus, chlorin or metal complexes can be a divalent aliphatic hydrocarbon group, the solution is physiologically acceptable and of a concentration suitable for intravenous or topical administration, or A solution that can be diluted to a suitable concentration. 2. A solution according to claim 1 of purpurin having the structure shown in FIG. 5 of the accompanying drawings. Aqueous emulsion or suspension. 3. Claim 1 of the purpurin metal complex having the structure shown in Figure 1 of the accompanying drawings Aqueous emulsions or suspensions of the solutions mentioned. 4. A solution according to claim 1 of chlorin having the structure shown in FIG. 6 of the accompanying drawings. Aqueous emulsion or suspension. 5. Claim 1 of the chlorin metal complex having the structure shown in Figure 2 of the accompanying drawings an aqueous emulsion or suspension of a solution of 6. As a new composition, chlorin having the structure of Figure 6 of the attached drawings or the attached figure A metal complex of chlorin having the structure shown in FIG. M is Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, G d, Hf, Ho, In, La, Lu, Mn, Mo, Nd, Ni, Pb, Pd, P r, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U , V, Y, Yb, Zn or Zr, and each of R1 to R13 is H or CHO, primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having children whose valences are both on the same carbon atom, and having 2 to 4 carbon atoms bonded to a carbon atom of a purine, chlorin or metal complex. a divalent aliphatic hydrocarbon group, Formula, R2N(R3)2 (wherein R2 is a carbon-to-carbon bond that is a single bond or a double bond) divalent aliphatic carbon having 1 to 4 carbon atoms and at most one double bond is a hydrogenated group, and R3 is hydrogen or an alkyl group having 1 to 2 carbon atoms. the two R3 groups can be the same or different), the formula R2N ( R4) 3+ (in the formula, R2 is a carbon-to-carbon bond that is a single bond or a double bond and is often a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, at least one of which is a double bond; , R4 is an alkyl group having 1 to 2 carbon atoms, and three R4 groups are the same radicals having the formula R2OH (wherein R2 is carbon 1 to 1, in which the prime-pair carbon bonds are single or double bonds, and at most one is a double bond; a divalent aliphatic hydrocarbon group having 4 carbon atoms, or CO2R', CH2CO2R' or CH2CH2CO2R' (wherein R' is H or a primary or secondary alkyl group having 1 to 4 carbon atoms) , only R1 has the valencies of the groups both on the same carbon atom, and having 2 to 4 carbon atoms bonded to carbon atoms of phosphorus, chlorin or metal complexes chlorin or metal complex of chlorin, which can be a divalent aliphatic hydrocarbon group . 7. As a novel composition, each of R10 to R13 is hydrogen, claim No. Chlorin or a metal complex of chlorin according to item 6. 8. As a novel composition, purpurin or the attached A purpurin metal complex having the structure shown in FIG. 1 of the drawings, in which: M is [there is an array] or Zr, and each of R1 to R13 is H or CHO, primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having children whose valences are both on the same carbon atom, and having 1 to 4 carbon atoms bonded to a carbon atom of a purine, chlorin or metal complex. a divalent aliphatic hydrocarbon group, Formula, R2N(R3)2 (wherein R2 is a carbon-to-carbon bond that is a single bond or a double bond) divalent aliphatic carbon having 1 to 4 carbon atoms and at most one double bond is a hydrogenated group, and R3 is hydrogen or an alkyl group having 1 to 2 carbon atoms. and the two R3 groups can be the same or different), the formula R2N (R4)3+ (wherein R2 is a carbon-to-carbon bond that is a single bond or a double bond, and Divalent aliphatic hydrocarbon group having 1 to 4 carbon bonds, at least one of which is a double bond , R4 is an alkyl group having 1 to 2 carbon atoms, and three R4 groups are groups having the formula R2OH (which can be the same or different), in which R2 is Carbon-to-carbon bonds are single or double bonds, with at most one double bond 1 a divalent aliphatic hydrocarbon group having ~4 carbon atoms), or , CO2R', CH2CO2R' or CH2CH2CO2R' (wherein R' is H or a primary or secondary alkyl group having 2 to 4 carbon atoms) and R1 is the only one in which the valences of the groups are both on the same carbon atom, and having 2 to 4 carbon atoms bonded to carbon atoms of phosphorus, chlorin or metal complexes purpurin or purpurin metal, which can be a divalent aliphatic hydrocarbon radical Complex. 9. As a novel composition, each of R10 to R13 is hydrogen, claim No. Purpurin or a metal complex of purpurin according to item 8. 10. Purpudding having the structure shown in Fig. 5 of the attached drawings, and having the structure shown in Fig. 1 of the attached drawings. a metal complex of purpurin having the structure shown in FIG. 6 of the accompanying drawings, and administers to a human patient an effective amount of a metal complex of chlorin having the structure shown in Figure 2 of the accompanying drawings. A method for detecting and treating a tumor comprising providing in said structure: M is Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, G d, Hf, Ho, In, La, Lu, Mn, Mo, Nd, Ni, Pb, Pd, P r, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U , V, Y, Yb, Zn or Zr, and each of R1 to R13 is H or CHO, primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having children whose valences are both on the same carbon atom, and having 1 to 4 carbon atoms bonded to a carbon atom of a purine, chlorin or metal complex. a divalent aliphatic hydrocarbon group, Formula, R2N(R3)2 (R2 is a carbon-to-carbon bond is a single bond or a double bond; Divalent aliphatic hydrocarbons having 1 to 4 carbon atoms, at most one double bond group, R3 is hydrogen or an alkyl group having 1 to 2 carbon atoms, and 2 groups having the formula R2N (R4 )3+ (wherein, R2 is a carbon-to-carbon bond that is a single bond or a double bond and is at most a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, one of which is a double bond; , R4 is an alkyl group having 1 to 2 carbon atoms, and the three R4 groups are the same or a group having the formula R2OH (wherein R2 is a carbon pair 1 to 4 carbon bonds, single or double, with at most one double bond is a divalent aliphatic hydrocarbon group having carbon atoms, or CO2R', CH2CO2R' or CH2CH2CO2R' (wherein R' is H or a primary or secondary alkyl group having 1 to 4 carbon atoms) and R1 is the only one in which the valences of the groups are both on the same carbon atom, and having 2 to 4 carbon atoms bonded to carbon atoms of phosphorus, chlorin or metal complexes A method for detecting and treating tumors, which can be divalent aliphatic hydrocarbon groups. 11. Claim 1 for detecting a tumor, including the additional step of irradiating the patient with ultraviolet light. The method described in item 0. 12. The purpurin, chlorin, or metal complex administered to the patient has an absorbance peak. Claims for treating tumors that include an additional step of irradiating the patient with visible light at wavelengths that The method according to item 10. 13. Purpudding having the structure shown in Fig. 5 of the attached drawings, and having the structure shown in Fig. 1 of the attached drawings. a purpurin metal complex having the structure shown in Figure 6 of the accompanying drawings; Administering to an animal patient an effective amount of a metal complex of chlorin having the structure shown in Figure 2 of the accompanying drawings. A method for detecting and treating a tumor comprising: is [there is an array] or Zr, and each of R1 to R13 is H or CHO, primary or secondary alkyl groups having 1 to 4 carbon atoms, 2 to 4 carbon atoms an alkylene group having children whose valences are both on the same carbon atom, and having 1 to 4 carbon atoms bonded to a carbon atom of a purine, chlorin or metal complex. a divalent aliphatic hydrocarbon group, Formula, R2N(R3)2 (R2 is a carbon-to-carbon bond is a single bond or a double bond; Divalent aliphatic hydrocarbons having 1 to 4 carbon atoms, at most one double bond group, R3 is hydrogen or an alkyl group having 1 to 2 carbon atoms, and 2 groups having the formula R2N (R4 )3+ (wherein, R2 is a carbon-to-carbon bond that is a single bond or a double bond and is at most a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, one of which is a double bond; , R4 is an alkyl group having 1 to 2 carbon atoms, and the three R4 groups are the same or a group having the formula R2OH (wherein R2 is a carbon pair 1 to 4 carbon bonds, single or double, with at most one double bond is a divalent aliphatic hydrocarbon group having carbon atoms, or CO2R', CH2CO2R' or CH2CH2CO2R' (wherein R' is H or a primary or secondary alkyl group having 1 to 4 carbon atoms) and R1 is the only one in which the valences of the groups are both on the same carbon atom, and having 2 to 4 carbon atoms bonded to carbon atoms of phosphorus, chlorin or metal complexes A method for detecting and treating tumors, which can be divalent aliphatic hydrocarbon groups. 14. Claims for detecting tumors, including an additional step of irradiating the patient with ultraviolet light The method described in box 13. 15. The purpurin, chlorin, or metal complex administered to the patient has an absorbance peak. Claims for treating tumors that include an additional step of irradiating the patient with visible light at wavelengths that The method according to item 13.