JPWO2011099602A1 - Porphyrin derivatives and their use in radiodynamic therapy - Google Patents

Abstract

An antitumor agent comprising the porphyrin compound, wherein the porphyrin compound represented by the following formula I is used to irradiate radiation when accumulated in a tumor tissue of a mammal.

Description

  The present invention relates to photodynamic therapy using radiation and compounds used in the therapy.

Cyclic tetrapyrroles such as chlorophyll have absorption at around 670 nm, and the fluorescence emission is relatively strong in the monomer state, so sensitization for promising photodynamic therapy (PDT) It is expected as an agent. PDT is a treatment method that has been clinically applied to the treatment of cancer in recent years. This treatment method involves irradiating a photosensitizer accumulated in a tumor tissue with light to cause necrosis of the tumor tissue, and an application for an invention relating to photodynamic therapy using a porphyrin derivative has been made (patent) Reference 1).
The PDT therapeutic agents Photofrin (registered trademark) and Laserphyrin (registered trademark) have already been clinically applied using light irradiation in the visible light region. In addition, by utilizing the accumulation of PDT therapeutics in tumors, radioactive isotopes such as iodine are added to the photosensitizer 2- [1-hexyloxyethyl] -2-devinyl pyropheophorbide-a (HPPH), etc. It has also been developed as a diagnostic imaging agent that identifies the location of the primary tumor or metastatic tumor in the body using PET or MRI (Non-Patent Documents: 1, 2, 3). In addition, Chlorophyll is a porphyrin derivative with a longer absorption wavelength that is more permeable than Photofrin, and its product pyropheophorbide is incorporated inside mitochondria and attacks tumor cells, so it is expected to have a stronger antitumor effect (Non-patent documents: 4, 5, 6).

  On the other hand, iodine and bromine compounds are taken up by cancer cells and augmented using Auger electrons generated by irradiating X-rays with energy equivalent to the K absorption edge of the element (33.17 keV in the case of iodine). There is radiation therapy that obtains a sensitive effect. This is called photon activation therapy (PAT) (non-patent documents: 7, 8). This therapy is a radiotherapy that obtains a sensitizing effect using Auger electrons generated by incorporating iodine or bromine compounds into cancer cells and irradiating X-rays with energy equivalent to the K absorption edge of the element. is there.

  However, cancer treatment by irradiation using these drugs has not been realized yet. In other words, since conventional PDT treatment uses infrared light, light reaches only a deep tissue of about 10 mm. For this reason, treatment was possible only for surface tumors such as skin, digestive organs, and bronchi. That is, the primary primary tumor on the surface layer was the subject. Treatment of tumors with a poorer prognosis such as cancers derived from deep tissues and metastases has been extremely difficult. In addition, radiation therapy can reach the deep part, but there is a problem that exposure to surrounding tissues is a problem, and there is an upper limit on the total irradiation dose to the patient, so that it cannot be repeatedly treated.

International Publication 2006/005924 International Publication 2009/105210

Multimodality agents for tumor imaging (PET, fluorescence) and photodynamic therapy.A possible "see and treat" approach.Pandey SK, Gryshuk AL, Sajjad M, Zheng X, Chen Y, Abouzeid MM, Morgan J, Charamisinau I, Nabi HA, Oseroff A, Pandey RK. J Med Chem. 2005 Oct 6; 48 (20): 6286-95. Comparative positron-emission tomography (PET) imaging and phototherapeutic potential of 124I- labeled methyl- 3- (1'-iodobenzyloxyethyl) pyropheophorbide-a vs the corresponding glucose and galactose conjugates.Pandey SK, Sajjad M, Chen Y, Zheng X, Yao R, Missert JR, Batt C, Nabi HA, Oseroff AR, Pandey RK. J Med Chem. 2009 Jan 22; 52 (2): 445-55. Compared to purpurinimides, the pyropheophorbide containing an iodobenzyl group showed enhanced PDT efficacy and tumor imaging (124I-PET) ability.Pandey SK, Sajjad M, Chen Y, Pandey A, Missert JR, Batt C, Yao R, Nabi HA, Oseroff AR , Pandey RK. Bioconjug Chem. 2009 Feb; 20 (2): 274-82. The role of subcellular localization in initiation of apoptosis by photodynamic therapy.Kessel D, Luo Y, Deng Y, Chang CK. Photochem Photobiol. 1997 Mar; 65 (3): 422-6. Comparison of photodynamic targets in a carcinoma cell line and its mitochondrial DNA-deficient derivative. Morgan J, Potter WR, Oseroff AR. Photochem Photobiol. 2000 Jun; 71 (6): 747-57. Mitochondria-based photodynamic anti-cancer therapy. Morgan J, Oseroff AR. Adv Drug Deliv Rev. 2001 Jul 2; 49 (1-2): 71-86. Review. Synchrotron radiation-based experimental determination of the optimal energy for cell radiotoxicity enhancement following photoelectric effect on stable iodinated compounds.Corde S, Joubert A, Adam JF, Charvet AM, Le Bas JF, Esteve F, Elleaume H, Balosso J. Br J Cancer 2004 Aug 2; 91 (3): 544-51. Optimal photon energies for IUdR K-edge radiosensitization with filtered x-ray and radioisotope sources.Karnas SJ, Yu E, McGarry RC, Battista JJ.Phys Med Biol. 1999 Oct; 44 (10): 2537-49.

  An object of this invention is to provide the photodynamic therapy using a radiation, and the compound used for the said therapy.

  As a result of intensive studies to solve the above problems, the present inventor found that a porphyrin compound added with iodine or the like is useful for photodynamic therapy by X-ray irradiation in a low energy region, and completed the present invention. It came to do.

That is, the present invention is as follows.
(1) The following formula I:

Wherein R ¹ , R ⁴ , R ⁷ and R ¹⁰ are each independently a hydrogen atom, an oxygen atom, an optionally substituted C _1-10 alkyl, or an optionally substituted C _{2 Represents -10} alkenyl, optionally substituted C _2-10 alkynyl, optionally substituted C _6-14 aryl or optionally substituted 5-14 membered heteroaryl, wherein The group is an oxygen atom, C _1-6 alkyl, and at least one selected from the group consisting of OR ²⁰ and COOR ²⁰ (R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl). And
R ² , R ⁵ , R ⁸ and R ¹¹ are each independently a hydrogen atom, an oxygen atom, an optionally substituted C _1-10 alkyl, an optionally substituted C _2-10 alkenyl, Represents optionally substituted C _2-10 alkynyl, optionally substituted C _6-14 aryl or optionally substituted 5-14 membered heteroaryl, wherein the substituent is oxygen Atoms, C _1-6 alkyl, and OR ³⁰ and COOR ³⁰ (R ³⁰ is a hydrogen atom, optionally substituted C _1-6 alkyl, optionally substituted C _2-10 alkenyl, optionally Represents an optionally substituted C _6-14 aryl, an optionally substituted C _7-20 arylalkyl or an optionally substituted 5-14 membered heteroaryl, each substituent having a K-shell absorption edge Group may be further substituted with one or more of the elements after element number 15 (P) showing 2 KeV or more. At least one selected et al.,
R ³ , R ⁶ , R ⁹ and R ¹² are each independently a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _6-14 aryl, C _7-20 aryl Represents alkyl, 5-14 membered heteroaryl, C _1-10 alkoxy, C _2-10 alkenyloxy, C _2-10 alkynyloxy, C _6-14 aryloxy or 5-14 membered heteroaryloxy, said alkyl, alkenyl , Alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy and heteroaryloxy are, optionally, C _1-6 alkyl, C _6-14 aryl, C _7-20 arylalkyl,- (CH ₂ CH ₂ O) _n -R ²⁰ ,-(CH ₂ ) _n -OR ²⁰ and-(CH ₂ ) _n -COOR ²⁰ (n is an integer of 0 to 6, and R ²⁰ is the same as above. And one of the elements after element number 15 (P) indicating that the K-shell absorption edge is 2 KeV or more. May be substituted with at least one member selected from the group consisting of a plurality, each substituent, C _1-6 alkyl, C _2-6 alkenyl, or K-shell absorption edge element number 15 that indicates the above 2 KeV (P ) May be further substituted with one or more of the following elements,
R ⁸ and R ⁹ can form a saturated or unsaturated 5-membered ring or 6-membered ring, and the ring is optionally an oxygen atom, C _1-6 alkyl and COOR ²⁰ (R ²⁰ is And may be substituted with at least one selected from the group consisting of:
M is a metal, silicon or hydrogen atom, the metal is Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, In, Sn, Sb, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Ac, Th, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No and Selected from Lr,

Represents a single bond or a double bond. )
An antitumor agent comprising the porphyrin compound, wherein the porphyrin compound is used to irradiate radiation when accumulated in a tumor tissue of a mammal.

In a preferred embodiment of the present invention, R ¹ , R ⁴ , R ⁷ and R ¹⁰ each independently represent a hydrogen atom or an optionally substituted C _1-10 alkyl, wherein the substituent is , An oxygen atom, C _1-6 alkyl, and at least one selected from the group consisting of OR ²⁰ and COOR ²⁰ (R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl). .

Further, in a preferred embodiment of the present invention, R ² , R ⁵ , R ⁸ and R ¹¹ each independently represent a hydrogen atom or an optionally substituted C _1-10 alkyl, wherein The group includes an oxygen atom, C _1-6 alkyl, and OR ³⁰ and COOR ³⁰ (R ³⁰ is a hydrogen atom, an optionally substituted C _1-6 alkyl, or an optionally substituted C _{6- 14} aryl, each substituent, K-shell absorption edge is selected from the group consisting of one or even may.) which is further substituted more with of atomic number 15 (P) after the element having a higher 2KeV At least one is mentioned.

Further, in a preferred embodiment of the present invention, R ³ , R ⁶ , R ⁹ and R ¹² are each independently a hydrogen atom, optionally substituted C _1-10 alkyl, optionally substituted. C _6-14 aryl, optionally substituted C _6-14 aryloxy, or optionally substituted 5-14 membered heteroaryl, each substituent is optionally C _1-6 alkyl , C _6-14 aryl, C _7-20 arylalkyl, — (CH ₂ CH ₂ O) _n —R ²⁰ , — (CH ₂ ) _n —OR ²⁰ and — (CH ₂ ) _n —COOR ²⁰ (n is 0 And R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl.), And an element number 15 (P) or later in which the K-shell absorption edge indicates 2 KeV or more. It may be substituted with at least one selected from the group consisting of one or more of them, and each substituent is C _1-6 alkyl, C _2-6 alkenyl, or an element having a K-shell absorption edge of 2 KeV or more. Number 15 P) may be further substituted with one or more of the following elements.

Further, in a preferred embodiment of the present invention, R ⁸ and R ⁹ can form a saturated or unsaturated 5-membered ring or 6-membered ring, and the ring is optionally an oxygen atom, C _1-6 alkyl And COOR ²⁰ (R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl) and may be substituted with at least one selected from the group consisting of

In the present invention, the porphyrin compound comprises C _6-14 aryl or C _7-20 arylalkyl substituted with one or more of the elements after element number 15 (P) having a K-shell absorption edge of 2 KeV or more. The inclusion is preferred. The element of element number 15 (P) or later having a K shell absorption edge of 2 KeV or more is selected from, for example, halogen, lanthanoid, Y, Tc, Ru, Ba, In, Cs, Pt, Au, and Tl. Preferably the halogen is I or Br. A preferred lanthanoid is, for example, Gd.

  Furthermore, as the porphyrin compound in the present invention, for example, one represented by any one of the following formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and XVI Is mentioned.

In the present invention, the radiation is preferably parametric monochromatic X-rays.

  (2) Furthermore, the present invention is a porphyrin compound represented by the following formulas IV, IX, XIII, XIV, XV or XVI.

  According to the present invention, a porphyrin compound for photodynamic therapy using radiation is provided. According to the present invention, it is possible to repeatedly irradiate a deep tissue tumor at a low dose by using X-rays having a constant wavelength. In addition, radiation-sensitive substances are specifically present in tumor cells, and irradiation treatment can be performed specifically while confirming the location of the tumor by MRI, PET, etc., and the side effects of exposure can be significantly reduced. Furthermore, in the photodynamic therapy using the infrared region, only the lesion on the surface layer up to 1 cm was treated, but all regions and metastasis sites of 10 cm or less, which is the size of a tumor normally assumed by using radiation, are surgically treated. It can be treated by radiology regardless of surgery. Furthermore, in the surgical field, for example, intraoperative irradiation before tumor removal during extraction surgery is made possible for the primary tumor site and the metastatic lesion. As a result, it is possible to obtain effects such as the outflow of tumor cells into blood and lymph during surgery, the effect of preventing tumor seeding, recurrence from the metastatic site, and the reduction of side effects due to dissection surgery.

  In addition, the compound of the present invention can be used for treatment of deep cancer tissue by low energy X-rays, and in contrast to a treatment performed with a small exposure dose, radiosensitization treatment and photodynamic therapy treatment. It is thought that the cancer therapy which can expect the effect of both of these will be enabled.

It is a figure which shows the cell growth suppression result 24 hours after irradiation when low energy (33.17 KeV) irradiation with the same wavelength was performed with respect to the HeLa cell using the compound of this invention. It is a figure which shows the cell growth suppression result 66 hours after irradiation when low energy (33.17 KeV) irradiation with the same phase was performed with respect to the HeLa cell using the compound of this invention. It is a figure which shows the cell growth suppression result 48 hours after irradiation when low energy (33.17 KeV) irradiation with the same wavelength was performed with respect to the HeLa cell using the compound of this invention. It is a figure which shows the cell growth suppression result 48 hours after irradiation when low energy (31.97KeV and 34.37KeV) irradiation with a single wavelength using the compound of this invention was performed with respect to the HeLa cell. It is a figure which shows the cell growth suppression result 72 hours after irradiation when low energy (33.17 KeV) irradiation with the same wavelength was performed with respect to the T24 cell using the compound of this invention. It is a figure which shows the cell growth suppression result 72 hours after irradiation when a HeLa cell and MCF7 cell are irradiated with the white X ray of 4MeV using the compound of this invention. Left panel: HeLa cells, right panel: MCF cells. It is a figure which shows the cell growth suppression result 72 hours after irradiation when a compound of the present invention is irradiated to MCF7 cells and T24 cells with 33 keV white X-rays. Left panel: MCF7 cells, right panel: T24 cells. It is a figure which shows the result of having performed the colony formation test of the cell when a HeLa cell and T24 cell were irradiated with the white X-ray of 33 keV using the compound of this invention. Upper panel: HeLa cells, lower panel: T24 cells. It is a figure which shows the result of having measured the number of living cells by the colorimetric determination using the reducing coloring reagent WST-8. It is a figure which shows the result of having evaluated the cell viability by a colony formation assay. It is a figure which shows the result of having measured active oxygen using fluorescent probe reagent APF.

Hereinafter, the present invention will be described in detail.
The present invention relates to photodynamic therapy with radiation (PDT), photosensitized therapy Photon Activation Therapy (PAT), and a compound used in the therapy, and a compound for PDT (porphyrin) to which iodine (I) or the like is added. Etc.) was completed based on the finding that when tumor cells were irradiated with single-wavelength X-rays at the iodine absorption edge, tumor growth was suppressed.

1. Overview As mentioned above, Photodynamic therapy (PDT) is a method in which a photosensitizer with tumor affinity is administered and irradiated with light, and singlet oxygen generated from this photosensitizer destroys the tumor. It is a treatment based on the mechanism. However, since the peak of the absorption wavelength of the photosensitive substance is in the visible light region, the PDT cannot be used for deep lesions, and there is a problem that indoor management that is shielded from light after administration is necessary. Therefore, the development of PDT using X-rays with biopermeability is desired.

  Therefore, the present inventor paid attention to iododeoxyuridine (IUdR), an iodo compound used in photon activation therapy (PAT), and added an element such as iodine to the PDT compound, and the X at the absorption edge thereof. It was expected that the PAT effect and the PDT effect were induced in the PDT compound by irradiating the line. That is, using a single wavelength X-ray of the iodine absorption edge, it was found that tumor cells administered with an iodine-added PDT compound showed growth inhibition, and considered that this would enable a novel anticancer treatment, leading to the present invention. .

  Therefore, the present invention causes a radiosensitization effect and induction of active oxygen, etc. by adding a specific element to a compound that induces photodynamic therapy or a compound that exhibits tumor accumulation and uses the absorption edge of the element. It is a technology that enables treatment of tumor lesions even in deep tissues.

  An experimental trial of treatment by adding a halogen or a metal to a PDT therapeutic agent and performing radiosensitization in the radiotherapy region has been made (Patent Documents 1 and 2). However, it is unclear whether these treatments can actually provide a therapeutic effect in the low energy X-ray region.

  In the present invention, treatment in a soft X-ray region or a low energy X-ray region (2-150 KeV) is possible, and treatment with 1/1000 energy of the conventional radiation treatment region is possible. X-rays in the low energy region have problems with radiation interference at the surface layer due to the penetration of deep tissue and the concentration of energy absorption at the surface tissue, but conversely, recently developed wavelengths have a single phase. Because it is possible to use X-rays with uniform alignment, radiation can be collected in a three-dimensional manner using a Frennel lens or the like, and it is possible to collect conventional X-rays using only a single wavelength. It is possible to prevent exposure due to extra wavelengths in X-ray irradiation. As a result, it was possible to overcome the points that were extremely difficult with the conventional treatment methods. That is, it is possible to reduce the exposure dose in normal tissues and to make it difficult to limit the total irradiation dose due to normal tissue tolerance.

2. Porphyrin Compound The porphyrin compound used in the present invention is a compound that induces photodynamic therapy or a compound that exhibits tumor accumulation, and is represented by the general formula (I).

In the above formula I, R ¹ , R ⁴ , R ⁷ and R ¹⁰ are each independently a hydrogen atom, an oxygen atom, an optionally substituted C _1-10 alkyl, and an optionally substituted C. _{Represents 2-10} alkenyl, optionally substituted C _2-10 alkynyl, optionally substituted C _6-14 aryl or optionally substituted 5-14 membered heteroaryl, wherein The substituent is at least one selected from the group consisting of an oxygen atom, C _1-6 alkyl, and OR ²⁰ and COOR ²⁰ (R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl). And selected from one or more of these groups of substituents.

In the present invention, preferably, R ¹ , R ⁴ , R ⁷ and R ¹⁰ each independently represent a hydrogen atom or an optionally substituted C _1-10 alkyl, wherein the substituent is , An oxygen atom, C _1-6 alkyl, and at least one selected from the group consisting of OR ²⁰ and COOR ²⁰ (R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl). .

R ² , R ⁵ , R ⁸ and R ¹¹ are each independently a hydrogen atom, an oxygen atom, an optionally substituted C _1-10 alkyl, an optionally substituted C _2-10 alkenyl, Represents optionally substituted C _2-10 alkynyl, optionally substituted C _6-14 aryl or optionally substituted 5-14 membered heteroaryl, wherein the substituent is oxygen It is at least one selected from the group consisting of an atom, C _1-6 alkyl, and OR ³⁰ and COOR ³⁰ . R ³⁰ is a hydrogen atom, an optionally substituted C _1-6 alkyl, an optionally substituted C _2-10 alkenyl, an optionally substituted C _6-14 aryl, an optionally substituted Represents an optionally substituted _C7-20 arylalkyl or optionally substituted 5- to 14-membered heteroaryl, each substituent having an element number of 15 (P) or later, wherein the K-shell absorption edge is 2 KeV or more. One or more of them (eg, I or Gd) may be further substituted.

In the present invention, preferably, R ² , R ⁵ , R ⁸ and R ¹¹ each independently represent a hydrogen atom or an optionally substituted C _1-10 alkyl, wherein the substituent is , An oxygen atom, C _1-6 alkyl, and OR ³⁰ and COOR ³⁰ (R ³⁰ is a hydrogen atom, an optionally substituted C _1-6 alkyl, or an optionally substituted C _6-14 aryl. And each substituent may be further substituted with one or more of the elements after element number 15 (P) having a K-shell absorption edge of 2 KeV or more. One.

R ³ , R ⁶ , R ⁹ and R ¹² are each independently a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _6-14 aryl, C _7-20 aryl Represents alkyl, 5-14 membered heteroaryl, C _1-10 alkoxy, C _2-10 alkenyloxy, C _2-10 alkynyloxy, C _6-14 aryloxy or 5-14 membered heteroaryloxy, said alkyl, alkenyl , Alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy and heteroaryloxy are, optionally, C _1-6 alkyl, C _6-14 aryl, C _7-20 arylalkyl,- (CH ₂ CH ₂ O) _n -R ²⁰ ,-(CH ₂ ) _n -OR ²⁰ and-(CH ₂ ) _n -COOR ²⁰ (n is an integer of 0-6, R ²⁰ is a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl.), and atomic number 1 to K-shell absorption edge exhibits more 2KeV (P) may be substituted with at least one member selected from the group consisting of one or more of the following elements. In addition, the substituent is further substituted with one or more of C _1-6 alkyl, C _2-6 alkenyl, or an element after element number 15 (P) whose K-shell absorption edge is 2 KeV or more. Also good.

In the present invention, preferably R ³ , R ⁶ , R ⁹ and R ¹² are each independently a hydrogen atom, an optionally substituted C _1-10 alkyl, an optionally substituted C _{6- 14} aryl, optionally substituted C _6-14 aryloxy, or optionally substituted 5-14 membered heteroaryl, each substituent is optionally C _1-6 alkyl, C _{6 -14} aryl, C _7-20 arylalkyl, — (CH ₂ CH ₂ O) _n —R ²⁰ , — (CH ₂ ) _n —OR ²⁰ and — (CH ₂ ) _n —COOR ²⁰ (where n is 0-6) R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl.), And one of the elements after element number 15 (P) whose K-shell absorption edge is 2 KeV or more. The substituent may be substituted with at least one selected from the group consisting of one or a plurality, and each substituent is C _1-6 alkyl, C _2-6 alkenyl, or element number 15 (K-shell absorption edge is 2 KeV or more) P) and later It may be further substituted with one or more of.

R ⁸ and R ⁹ can form, for example, a saturated or unsaturated 5-membered ring or 6-membered ring by a cyclization reaction, and the ring optionally includes an oxygen atom, C _1-6 alkyl, and COOR ²⁰ ( R ²⁰ is the same as defined above) and may be substituted with at least one selected from the group consisting of:

  M is a metal, silicon or hydrogen atom, the metal is Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, In, Sn, Sb, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Ac, Th, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No and Selected from Lr.

Represents a single bond or a double bond.

  In the present invention, the elements after the element number 15 (P) having a K shell absorption edge of 2 KeV or more are selected from, for example, halogen, lanthanoid, Y, Tc, Ru, Ba, In, Cs, Pt, Au, and Tl.

  In the present invention, “halogen” means a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br) or an iodine atom (I), preferably I or Br. In addition, “lanthanoid” means 15 elements from lanthanum of atomic number 57 to lutetium of 71, namely La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, preferably Gd.

In the present invention, “C _1-10 alkyl” and “C _1-6 alkyl” mean straight or branched hydrocarbon groups having 1 to 10 and 1 to 6 carbon atoms, respectively. To do. Examples of such an alkyl group include a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 2-methyl-1-propyl group (i-butyl group), a 2-methyl-2-propyl group ( t-butyl group), 1-butyl group, 2-butyl group, 1-pentyl group, hexyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, etc., preferably methyl group, ethyl Group, 1-propyl group, 2-propyl group and the like.

“C _2-10 alkenyl” and “C _2-6 alkenyl” mean straight or branched hydrocarbon groups having 1 to 10 and 2 to 6 carbon atoms, respectively. Has one bond. Examples of such alkenyl groups include ethenyl group (vinyl group), 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, pentenyl group and the like. It is done.

“C _2-10 alkynyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms and has one triple bond. Examples of such alkynyl groups include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group and the like.

“C _6-14 aryl” means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and an indenyl group, preferably It is a phenyl group.

“C ₇ -C ₂₀ arylalkyl” is preferably a C ₇ -C ₁₂ arylalkyl group. Examples of arylalkyl groups include benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenyl A pentyl etc. can be mentioned.

  “5- to 14-membered heteroaryl” is a fragrance having 5 to 14 atoms constituting a ring and containing 1 to 5 heteroatoms (nitrogen, oxygen or sulfur atoms) in the atoms. Means a group. Examples of such heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, furazanyl, thiadiazolyl, oxadiazolyl Group, pyridyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group and the like.

“C _1-10 alkoxy” is a group in which an oxygen atom is bonded to the terminal of C _1-10 alkyl. For example, methoxy group, ethoxy group, 1-propoxy group (n-propoxy group), 2-propoxy group ( i-propoxy group), 2-methyl-1-propoxy group (i-butoxy group), 2-methyl-2-propoxy group (t-butoxy group), 1-butoxy group (n-butoxy group), 2-butoxy Group (s-butoxy group), 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group and the like.

“C _2-10 alkenyloxy” means a group in which an oxygen atom is bonded to the terminal of C _2-10 alkenyl. For example, vinyloxy group, 1-ethylethenyloxy group, 2-propenyloxy group, 1-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group and the like can be mentioned.

“C _2-10 alkynyloxy” means a group having an oxygen atom bonded to the terminal of C _2-10 alkynyl. For example, ethynyloxy group, 1-propynyloxy group, 2-propynyloxy group, 1-butynyloxy group, 2-butynyloxy group, 3-butynyloxy group, 1-methyl-2-propynyloxy group, 1-ethyl-2-propynyl An oxy group etc. are mentioned.

“C _6-14 aryloxy” means a group in which an oxygen atom is bonded to the terminal of C _6-14 aryl, and examples thereof include a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.
“5- to 14-membered heteroaryloxy” means a group in which an oxygen atom is bonded to the terminal of a 5- to 14-membered heteroaryl, for example, pyridyloxy group, pyrazinyloxy group, pyrimidinyloxy group, imidazolyloxy group, pyrazolyloxy group, quinolyloxy Group, furfuryloxy group and the like.

In the present invention, the compound represented by the general formula (I) is a C _6-14 aryl substituted with one or more of elements after element number 15 (P) having a K-shell absorption edge of 2 KeV or more. It preferably contains C _7-20 arylalkyl. The elements after element number 15 (P) having a K shell absorption edge of 2 KeV or more are as described above.
Such compounds, for example the general formula is a C _1-10 alkyl R ² is optionally substituted compounds shown in ^{(I), OR 31 (R} 31 , for example, as a substituent, the K-shell absorption edge 2KeV And C _6-14 aryl or C _7-20 arylalkyl substituted with one or more of the elements after element number 15 (P) showing the above. A preferred substituent for R ³¹ is a benzyl group substituted with a halogen (eg, I) or a lanthanoid (eg, Gd).

In addition, one or more of R ³ , R ⁶ , R ⁹ and R ¹² of the compound represented by the general formula (I) is selected from the elements of element number 15 (P) and after that the K-shell absorption edge indicates 2 KeV or more. It may be one or more substituted C _6-14 aryl or C _7-20 arylalkyl, or _optionally substituted C _6-14 aryloxy, _optionally substituted 5-14 membered heteroaryl ( Pyridyl which may be substituted is preferable. The aryloxy and heteroaryl are C _1-6 alkyl, C _6-14 aryl, C _7-20 arylalkyl, — (CH ₂ CH ₂ O) _n —R ²⁰ , — (CH ₂ ) _n —OR ²⁰ and -(CH ₂ ) _n -COOR ²⁰ (n is an integer of 0 to 6, R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl), and the K-shell absorption edge is 2 KeV. It may be substituted with at least one selected from the group consisting of one or more of the elements after element number 15 (P) showing the above. Here, preferable substituents include, for example, a benzyl group or a phenyl group substituted with halogen (for example, I), and — (CH ₂ ) ₄ —COOH or — (CH ₂ CH ₂ O) ₃ —CH ₃ There may be.

  In the formula (I),

Represents a single bond or a double bond (7th and 8th positions, 17th and 18th positions in Formula I). In the case of a single bond, R is located at 7th and 8th positions and 17th and 18th positions, respectively. ^{In addition to 4} and R ⁵ , R ¹⁰ and R ¹¹ , a hydrogen atom is bonded. For example, both or one of the above positions can be a single bond to form chlorin or bacteriochlorin. In the present invention, such chlorin or bacteriochlorin can also be used.

  Examples of the compound used in the present invention include compounds represented by any of the following formulas II, III, IV, V, IX, X, XI, XII, XIII, XIV, XV and XVI, Examples thereof include compounds in which the porphyrin skeleton is represented by any one of VI, VII, and VIII.

In Formulas XII and XIV, “Me” represents a methyl group, and in Formula XV, “Et” represents an ethyl group.

The compound represented by the formula (I) (also referred to as “the compound of the present invention”) is prepared by reacting an aldehyde and pyrrole with an acid catalyst in a known method, for example, CHCl ₃ or CHCl ₂ to equilibrate porphynogen. After the formation, it can be synthesized by oxidation. Or a commercial item may be used for a compound and it can also synthesize | combine using the commercially available precursor compound.

  The above compounds are used to irradiate radiation when accumulated in mammalian tumor tissue or tumor cells. “Accumulate” means that the compound is distributed at a higher concentration than other tissues in or on the surface of tumor cells or cells surrounding the tumor, or in the matrix surrounding the tumor cells.

3. Methods of Treatment In another aspect of the present invention, the compound of formula (I) of the present invention is administered to a subject in need thereof, and radiation is administered when the compound accumulates in mammalian tumor tissue or tumor cells. A method of treating a tumor with photon activation therapy comprising the step of irradiating is provided.

  The subject is a human or non-human mammal. When a test subject is a human, it is preferably various cancer patients. Non-human mammals include, for example, pets, zoo animals, livestock, etc., and specifically cats, dogs, horses, cows, pigs, goats, sheep, birds, primates, elephants or felines Etc.

  The tumor to be treated is not particularly limited. For example, brain tumor, head and neck cancer, cervical cancer, jaw cancer, maxillary cancer, submandibular gland cancer, oral cancer (tongue cancer, oral floor cancer, gingival cancer, buccal mucosa Cancer, including hard palate cancer), sublingual gland cancer, parotid gland cancer, nasal cavity cancer, paranasal sinus cancer, laryngeal cancer, esophageal cancer, lung cancer, breast cancer, pancreatic cancer, gastric cancer, biliary tract cancer, small intestine or duodenal cancer, large intestine Cancer, bladder cancer, kidney cancer, liver cancer, prostate cancer, uterine cancer (including cervical cancer, endometrial cancer), ovarian cancer, thyroid cancer, pharyngeal cancer, various sarcomas (eg, osteosarcoma, chondrosarcoma, Kaposi sarcoma, Myoma, angiosarcoma, fibrosarcoma), malignant lymphoma (including Hodgkin lymphoma, non-Hodgkin lymphoma), leukemia (eg, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic Leukemia (CLL) and acute lymphocytic leukemia (ALL), lymphoma, multiple myeloma (MM) Bone marrow including atypical growth syndrome), skin cancer and melanoma, neuroblastoma, and the like.

  The compound of the present invention can be applied to the affected area as it is, or by any known method such as intravenous, intramuscular, intraperitoneal or subcutaneous injection, inhalation from the nasal cavity, oral cavity or lung, oral administration, catheter, etc. It can also be introduced into a living body (cells or organs of interest) by intravascular administration or the like. Furthermore, the compound of the present invention can be used in combination with other substances having other antitumor activity (other antitumor agents). In this case, the compound of the present invention and the other antitumor agent can be administered simultaneously, or can be introduced into a living body by a method in which one is administered and the other is administered after a lapse of a certain time.

  In addition, the compound of the present invention may be used as it is after, for example, freeze-drying or the like, or a known pharmaceutically acceptable carrier such as an excipient, a bulking agent, a binder or a lubricant, It can be mixed with additives (including buffering agents, tonicity agents, chelating agents, coloring agents, preservatives, fragrances, flavoring agents, sweetening agents, etc.).

  Depending on the mode of oral administration or parenteral administration, the compound of the present invention can be administered orally, such as tablets, capsules, powders, granules, pills, solutions, syrups, injections, external preparations, suppositories, It can be in the form of a parenteral administration agent such as an eye drop.

  Furthermore, when a solvate and an optical isomer are present, the compound of the present invention includes the solvate and the optical isomer. Examples of solvates include hydrates and non-hydrates, and hydrates are preferred. Examples of the solvent include water, alcohol (eg, methanol, ethanol, n-propanol, etc.), dimethylformamide and the like.

  Furthermore, the compounds of the present invention may form pharmacologically acceptable salts with acids or bases. Examples of the salt with an acid include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, or formic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, and tartaric acid. And organic acid salts such as stearic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid. Examples of the salt with a base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N′- Examples thereof include organic base salts such as dibenzylethylenediamine, arginine and lysine, and ammonium salts. Furthermore, the compound of the present invention may be crystalline or non-crystalline, and when a crystalline polymorph exists, it may be a single substance or a mixture of any of those crystalline forms.

  The dose of the compound of the present invention is not limited to factors such as the patient's age, weight, height, sex, medical condition, past medical history, as well as the site and extent of the disease to be treated, the target site. It can be changed according to factors such as the degree and rate of accumulation of the compound of the invention and the removal rate of the compound represented by formula (I).

  The amount of the compound represented by formula (I) administered to the subject is not particularly limited as long as it is present in an amount sufficient to cause tumor cell damage, cell death or necrosis upon X-ray irradiation.

For example, the dosage is 0.1 mg / kg to 100 mg / kg, preferably 1 mg / kg to 50 mg / kg, more preferably 5 mg / kg to 25 mg / kg.
The compound is preferably uniformly distributed inside the tumor tissue, and the tumor tissue accumulation ratio (Tumor-to-background ratio: T / BG ratio) of the compound is 1: 1 to 500: 1, preferably 10: 1. ~ 200: 1, more preferably 20: 1 to 150: 1.

  The compound of the present invention can be used in combination with laser therapy, proton therapy, non-proton therapy, pion therapy, and the like.

  The compound can be administered to the patient prior to irradiation. Usually, the compounds can be administered 10 minutes to 96 hours before radiation treatment, preferably 180 minutes to 48 hours before. When the above time has elapsed after administration of the compound, the compound accumulates in the tumor tissue or tumor cells to such an extent that the tumor cells are killed by irradiation.

Whether or not the compound is accumulated in mammalian tumor tissue or tumor cells is confirmed by a known method such as positron emission tomography (PET) or magnetic resonance imaging system (MRI). be able to.
The compound can be administered daily, at intervals of 2-6 days, preferably at intervals of 7 days, or at irregular intervals so that a therapeutically effective amount is maintained within the tumor tissue.

  The X-ray irradiated in the present invention has an energy of 1 keV to 1000 keV, and a preferable range is 20 keV to 150 keV.

  The radiation used in the present invention may be a commonly used radiation such as ionizing radiation, but is preferably parametric monochromatic X-ray. Parametric monochromatic X-rays have strong directivity and can be focused by a Fresnel lens (I. Sato, et al., Proceeding of the 5th Annual Meeting of Particle Accelerator Society of Japan and the 33th Linear Accelerator Meeting in Japan (2008) 64-68). Thereby, the pinpoint irradiation to the tumor becomes possible, and the tumor can be destroyed more effectively. Furthermore, since it is monochromatic (single wavelength), the wavelength of only the absorption edge that is more absorbed by the compound can be used compared to the conventional ionizing radiation being white (mixed wavelength). This makes it possible to dramatically reduce the total exposure dose.

  The ionizing radiation can be irradiated from a heavy ion beam, a gamma knife, an electron beam, a proton beam, a fast neutron beam, or the like.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Compound synthesis (1) Compound represented by formula (V)

The above compound was synthesized as follows.

Pyrrole (104 μL, 1.50 mmol) and 4-iodobenzaldehyde (350 mg, 1.5 mmol) were placed in a three-necked flask, the container was vacuum degassed, and the container was filled with argon. CHCl ₃ (150 mL) and then BF ₃ .OEt ₂ (62 mL, 0.50 mmol) were added to the vessel, and the mixture was stirred at room temperature in the dark for 1 hour. Thereafter, 2,3-dichloro-5,6-dicyanobenzoquinone (678 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour in the dark, and triethylamine (69 mL) was added. Perform column chromatography twice (first time: Al ₂ O ₃ , CHCl ₃ , 1% ethyl acetate. Second time: SiO ₂ , CHCl ₃ ), wash the resulting solid with hexane and filter to obtain a purple solid. Collected (118 mg, 0.110 mmol, 28%).

¹ H-NMR (CDCl ₃ , TMS): δ (ppm) = 8.85 (8H, s, β), 8.11, (8H, d, J = 8.3 Hz, PhH), 7.94 (8H, d, J = 8.3 Hz , PhH), -2.89 (2H, s, NH). LDI-MS: m / z = 1117.9 ([M] ⁺ ). TLC (SiO ₂ , CHCl ₃ ): R _f = 0.84

(2) Compound represented by formula (IV)

Bis (4-methyl-3-ethyl-2-pyrrole) methane (446 mg, 2.0 mmol) and 4-iodobenzaldehyde (464 mg, 2.0 mmol) were placed in a three-necked flask, and the container was vacuum degassed and then filled with argon. . CH ₂ Cl ₂ (350 mL) was added to the container, trifluoroacetic acid (9 drops with a pipette) was added, and the mixture was stirred at room temperature in the dark for 20 hours. Then, chloranil (739 mg, 3.00 mmol) was added, and after refluxing at room temperature in the dark for 6 hours, triethylamine (4 mL) was added. The reaction solution was concentrated to 50 mL, 10 g of florisil was added, and the solvent was distilled off. The obtained powder was put on the top of the SiO ₂ column, column chromatography (SiO ₂ , CHCl ₃ ) was performed, and the separated product was washed with methanol and filtered to obtain a purple solid (254 mg, 0.29 mmol, 29%).

¹ H-NMR (CDCl ₃ ): d (ppm) = 10.23 (2H, s, meso), 8.10 (4H, d, J = 8.2 Hz, PhH), 7.83 (4H, d, J = 8.2 Hz, PhH) , 4.02 (8H, q, J = 7.7 Hz, CH ₂ ), 2.53 (12H, s, CH ₃ ), 1.77 (12H, t, J = 7.7 Hz, CH ₃ ), -2.48 (2H, s, NH) LDI-MS: m / z = 883.2 ([MH] ⁺ ). TLC (SiO ₂ , CH ₂ Cl ₂ ): R _f = 0.27.

(3) Compound represented by formula (II) (X = I) (531 compound)

Methyl pheophorbide A synthesized as described above for compound 531 can be purchased from, for example, Wako Pure Chemical Industries. Methyl pheophorbide A 500 mg (Wako Pure Chemical Industries, Ltd.) was dissolved in 100 mL collidine and heated to reflux for 2 hours under a nitrogen atmosphere. After the reaction, collidine was removed by distillation under reduced pressure, and the residue was placed on an alumina column and separated and purified with methylene chloride. The eluted fractions were collected and methylene chloride was removed by distillation under reduced pressure, and then the residue was recrystallized from methanol / methylene chloride to synthesize methyl pyropheophorbide A (455 mg, 91% yield). 100 mg of methyl pyropheophorbide A was added to 2 mL of 30% hydrogen bromide / acetic acid and stirred at room temperature for 2 hours. After the reaction, the solvent was removed by distillation under reduced pressure using a vacuum pump, the residue was dissolved in 5 mL of m-iodobenzyl alcohol, and 10 mL of dehydrated methylene chloride and 40 mg of anhydrous potassium carbonate were added. The reaction solution was stirred at room temperature for 45 minutes under a nitrogen atmosphere. After the reaction, 200 mL of methylene chloride was added and transferred to a separatory funnel, and 100 mL of saturated sodium hydrogen carbonate was added to separate the solution. After collecting the organic layer, separation with 200 mL of water was repeated twice. The organic layer was collected and dried by adding sodium sulfate. The solvent was removed by distillation under reduced pressure, the residue was subjected to silica gel column chromatography, m-iodobenzyl alcohol was removed with 20% hexane / ethyl acetate, and the organic layer was recovered with 50% hexane / ethyl acetate. The recovered organic layer was distilled under reduced pressure to remove the solvent, thereby obtaining 115 mg of Compound 531 in a yield of 80%.
¹ H NMR (CDCl ₃ ): δ 9.76, 9.55 and 8.56 (all s, 1H, meso-H), 7.76 (s, 1H, ArH), 7.64 (d, J = 6.8, 1H, ArH), 7.30 (d , J = 8.0, 1H, ArH), 7.05 (t, J = 8.2, 1H, ArH), 6.00 (q, J = 6.9, 1H, 3 ¹ -H), 5.28 (d, J = 19.8, 1H, 13 ² -CH ₂ ), 5.13 (d, J = 19.8, 1H, 13 ² -CH ₂ ), 4.70 (d, J = 12.0, 1H, OCH ₂ Ar), 4.56 (dd, J = 3.2,11.6, 1H, OCH ₂ Ar), 4.48-4.53 (m, 1H, 18-H), 4.30-4.33 (m, 1H, 17-H), 3.72 (q, J = 8.0, 2H, 8-CH ₂ CH ₃ ), 3.69 , 3.61, 3.38 and 3.21 (all s, all 3H, for 17 ³ -CO ₂ CH ₃ and 3 × ring CH ₃ ), 2.66-2.74, 2.52-2.61, and 2.23-2.37 (m, 4H, 17 ¹ and 17 ² -H), 2.18 (dd, J = 2.8, 6.4, 3H, 3 ² -CH ₃ ), 1.83 (d, J = 8.0, 3H, 18-CH ₃ ), 1.72 (t, J = 7.6, 3H, 8-CH ₂ CH ₃ ), 0.41 (brs, 1H, NH), -1.71 (brs, 1H, NH) .HRMS for C ₄₁ H ₄₃ N ₄ O ₄ I: 782.2329 (calcd), 783.2407 (found, MH +) .

(4) Compound represented by formula (III) (717 compound)

Compound 717 was synthesized as follows.
200 mg of compound 531 was dissolved in a mixed solvent of 25 mL of THF and 8 mL of methanol, 400 mg of lithium hydroxide and 12 mL of water were added, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. The reaction solution was neutralized with 2% aqueous acetic acid solution, separated and extracted with 100 mL of methylene chloride. The organic layer was collected and further separated twice with 100 mL of water. The organic layer was collected, dried by adding sodium sulfate, and methylene chloride was concentrated by distillation under reduced pressure and reprecipitated with hexane to obtain 185 mg of Compound 717 in a yield of 95%.

¹ H-NMR (CDCl ₃ ): δ 9.72, 9.44 and 8.53 (all s, 1H, meso-H); 7.74 (s, 1H, ArH); 7.61 (d, J = 8.0, 1H, ArH); 7.28 ( 7.03 (m, 1H, ArH); 5.95 (q, J = 6.8, 1H, 3 ¹ -H); 5.25 (d, J = 20.0, 1H, 132-CH ₂ ); 5.10 ( d, J = 20.0, 1H, 13 ² -CH ₂ ); 4.65 (dd, J = 4.0,12.0, 1H, OCH ₂ Ar); 4.50 (m, 2H, OCH ₂ Ar &18-H); 4.28 (d , J = 7.6, 1H, 17-H); 3.67 (q, J = 7.6, 2H, 8-CH ₂ CH ₃ ); 3.58, 3.34 and 3.18 (all s, all 3H, for 3 × ring CH ₃ ); 2.55-2.72 and 2.20-2.35 (m, 4H, 17 ¹ and 17 ² -H); 2.15 (m, 3H, 3 ¹ -CH ₃ ); 1.78 (d, J = 7.6, 3H, 18-CH ₃ ); 1.68 (t, J = 7.2, 3H, 8-CH ₂ CH ₃ ); 0.02 (brs, 1H, NH); -1.70 (brs, 1H, NH). HRMS for C ₄₀ H ₄₁ N ₄ O ₄ I: 768.2174 (Calculated); 769.2207 (Found, MH +).
(5) Compound represented by formula IX

P-iodobenzyl bromide (1.9 g, 6.4 mmol) is added to DMF solution (15 mL) of 5,10,15,20-tetrapyridylporphyrin (30 mg, 0.049 mmol) heated to 80 ° C, and 2 hours under argon Refluxed. The reddish brown suspension was cooled to room temperature and diethyl ether (50 mL) was added. The precipitate was collected by centrifugation and washed with chloroform and methanol to obtain Target 2 (Formula IX) (57 mg, 0.032 mmol, 65%).

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 9.65 (8H, d, J = 5.5 Hz, o-Py), 9.21 (8H, bs, β), 9.02 (8H, d, J = 6.4 Hz, m-Py), 8.02 (8H, d, J = 8.3 Hz, m-benzyl), 7.72 (8H, d, J = 8.3 Hz, o-benzyl), 6.18 (8H, s, CH ₂ ),- 3.13 (2H, bs, NH). LDI-MS: m / z = 1051 (C ₅₄ H ₃₇ I ₂ N ₈ [M-2 (Ph-CH ₂ -I) -H] ⁺ ). ES-HRMS: m / z calcd for C ₆₈ H ₄₉ I ₄ N ₈ [MH] ³⁺ , 495.0086; found, 495.0070; calc for C ₆₁ H ₄₄ I ₃ N ₈ [M- Ph-CH ₂ -I] ³⁺ , 423.0274; found , 423.0262.

(6) Compound represented by Formula XII

A chloroform solution (230 mL) of 3-iodophenyldipyrromethane (0.80 mg, 2.3 mmol) and 4- (1,4,7,10-tetraoxaundecyl) benzaldehyde (620 mg, 2.3 mmol) was degassed with argon for 25 minutes, and BF3OEt2 ( 28.5 μL, 0.23 mmol) was added and stirred for 1 hour. After adding p-chloranil (841 mg, 3.4 mmol) and further stirring for 23 hours, triethylamine (28.5 μL, 0.20 mmol) was added and further stirred for 20 minutes. The brown solution was concentrated to about 10 mL, Florisil (10 g) was added, the solvent was distilled off, the brown powder obtained was spread on silica gel and eluted with chloroform: methanol = 50: 1. The purple solid obtained by distilling off the solvent was washed with methanol to obtain the desired product (30 mg, 0.022 mmol, 2%).

¹ H-NMR (CDCl ₃ ): δ (ppm) = 8.89 (4H, d, J = 4.6 Hz, β), 8.81 (4H, d, J = 4.6 Hz, β), 8.59 (2H, s, phenyl) , 8.18 (2H, d, J = 6.9 Hz, phenyl), 8.11 (6H, t, J = 8.4 Hz, phenyl), 7.48 (2H, t, J = 7.6 Hz, phenyl), 7.30 (4H, d, J = 8.4 Hz), 4.43 (4H, t, J = 4.6 Hz, CH ₂ ), 4.06 (4H, t, J = 5.3 Hz, CH ₂ ), 3.89 (4H, t, J = 4.6, CH ₂ ), 3.79 (4H, t, J = 6.1 Hz, CH ₂ ), 3.74 (4H, t, J = 4.6 Hz, CH ₂ ), 3.62 (4H, t, J = 4.6 Hz, CH ₂ ), 3.42 (6H, s, CH ₃ ), -2.81 (2H, s, NH). APCI-HRMS: m / z calcd for C ₅₈ H ₅₆ I ₂ N ₄ O ₈ [MH] ⁺ , 1191.2221; found, 1191.2222. TLC (chloroform: methanol = 20: 1): R _f = 0.17.

(7) Compound represented by Formula XIII

Add 5,10,15,20-tetrapyridylporphyrin (92 mg, 0.13 mmol) p-iodobenzyl bromide (533 mg, 1.8 mmol) to chloroform / ethanol (30 mL, 3/1) solution, and warm to 80 ° C. At reflux for 2 hours. This brown solution was directly subjected to column chromatography (SiO ₂ , chloroform / methanol = 4 / 1-2 / 1) to obtain the desired product 3 (Formula XIII) (48 mg, 0.052 mmol, 40%).

¹ H-NMR (CDCl ₃ / CD ₃ OD): δ (ppm) = 9.51 (2H, d, J = 6.4 Hz, m-Py), 9.43 (6H, d, J = 5.5 Hz, o-Py), 8.96 (8H, bs, β), 8.89 (2H, d, J = 6.4 Hz, o-Py), 8.27 (6H, d, J = 5.5 Hz, m-Py), 8.01 (2H, d, J = 8.3 Hz, m-benzyl), 7.63 (2H, d, J = 8.3 Hz, o-benzyl), 6.20 (2H, s, CH ₂ ). ESI-HRMS: m / z calcd for C ₄₇ H ₃₂ IN ₈ [M ] ⁺ , 835.1795, found, 835.1779.

(8) Compound represented by formula XIV

80 ^o C in warm porphyrin 3 (Formula XIII) (26 mg, 0.028 mmol ) iodomethane in DMF solution (15 mL) of (2.1 mL, 34 mmol) was added, under argon, and stirred for 2 hours at 100 ° C. The brown solution was cooled to room temperature, diethyl ether (70 mL) was added, and the resulting precipitate was separated by centrifugation and washed several times with chloroform to obtain the desired product 4 (Formula XIV) (31 mg, 0.023 mmol, 82 %).

¹ H-NMR (DMSO-d ₆ ): δ = 9.64 (2H, d, J = 6.4 Hz, m-Py), 9.49 (6H, d, J = 6.4 Hz, m-Py,), 9.26 (2H, bs, β), 9.20 (6H, bs, β), 9.04 (2H, d, J = 7.3 Hz, o-Py), 9.00 (6H, d, J = 6.4 Hz, o-benzyl), 8.02 (2H, d, J = 8.3 Hz, m-benzyl), 7.74 (2H, d, J = 8.3 Hz, o-benzyl), -3.12 (2H, bs, NH). ESI-HRMS: m / z calcd for C ₄₃ H ₃₅ N ₈ [M- (Ph-CH ₂ -I) -Br-3I] ⁺ , 663.2985; found, 663.2967; calcd for C ₅₀ H ₄₁ I ₁ N ₈ [M-Br-3I] ²⁺ , 440.1250; found , 440.1217; calcd for C ₄₂ H ₃₂ N ₈ [M-2CH ₃ -2 (C ₇ H ₆ I) -Br-3I] ²⁺ , 324.1375, found, 324.1361.

(9) Compound represented by Formula XV

P-iodobenzylbromide (1.4) was added to DMF solution (15 mL) of 5- (N- (4- (ethoxycarbonyl) butyl) pyridinium) -10,15,20-tripyridylporphyrin bomide (31 mg, 0.037 mmol) warmed to 80 ° C. g, 4.6 mmol) and refluxed under argon for 1.5 hours. The brown solution was cooled to room temperature, diethyl ether (100 mL) was added, and the resulting precipitate was separated by centrifugation and washed several times with chloroform to obtain the desired product 5 (Formula XV) (36 mg, 0.021 mmol, 57 %).

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 9.66 (6H, d, J = 6.4 Hz, m-Py), 9.58 (2H, d, J = 6.4 Hz, m-Py), 9.23 ( 8H, bs, β), 9.03 (8H, m, o-Py), 8.02 (6H, d, J = 8.3 Hz, o-benzyl), 7.73 (6H, d, J = 8.3 Hz, m-benzyl), 6.19 (6H, s, CH ₂ ), 4.99 (2H, t, J = 7.8 Hz, CH ₂ ), 4.15 (2H, q, J = 7.3 Hz, CH ₂ ), 2.57 (2H, q, J = 7.8 Hz , CH ₂ ), 2.31 (2H, q, J = 7.3 Hz, CH ₂ ), 1.87 (2H, q, J = 7.3 Hz, CH ₂ ), 1.26 (2H, t, J = 7.3 Hz, CH ₃ ), -3.12 (2H, bs, NH). ESI-HRMS: m / z calcd for C ₆₁ H ₄₉ I ₂ N ₈ O ₂ [MC ₇ H ₆ I-3Br] ⁺ , 1179.2068, found, 1179.2063; calcd for C ₅₄ H ₄₄ IN ₈ O ₂ [M-2 (C ₇ H ₆ I) -H-2Br] ⁺ , 963.2632, found, 963.2606.

(10) Compound represented by formula XVI

Porphyrin 5 (Formula XV) (30 mg, 0.017 mmol) in 1 N HCl (3.5 mL) was refluxed for 1.5 hours. The green solid produced by distilling off the solvent was washed with acetone and chloroform to obtain eye liquid 6 (Formula XVI) (25 mg, 0.015 mmol, 88%).

¹ H-NMR (CD ₃ OD): δ (ppm) = 9.49 (8H, t, J = 6.4 Hz, m-Py), 9.15 (8H, bs, β), 8.98 (8H, t, J = 6.4 Hz) , o-Py), 8.01 (6H, d, J = 8.3 Hz, o-benzyl), 7.63 (6H, d, J = 7.3 Hz, m-benzyl), 6.18 (6H, s, CH ₂ ), 5.03 ( 2H, t, J = 7.3 Hz, CH ₂ ), 2.53 (2H, t, J = 7.3 Hz, CH ₂ ), 2.40 (2H, q, J = 7.3 Hz, CH ₂ ), 1.94 (2H, q, J = 7.3 Hz, CH ₂ ). ESI-HRMS: m / z calcd for C ₅₂ H ₄₁ IN ₈ O ₂ ⁺ [M-2 (C ₇ H ₆ I) -4Br-H] ⁺ , 935.2313; found, 935.2308.

5 mg of 531 or 717 compound of the cell growth inhibition test powder was taken and placed in a 2 ml tube. It was dissolved in Dimethyl sulfoxide minimun 99.5% GC (DMSO) as a solvent to make 10 mg / ml. This was diluted with Dulbecco's modified Eagle's medium (DMEM), MEM medium (MEM), etc. to make final concentrations of 100 μg / ml and 10 μg / ml.

HeLa cell line (human cervical adenocarcinoma) or T24 cell line (human bladder transitional-cell carcinoma), etc. can be added to any cell in a 96-well plate, 12-well plate, or 6-well plate. The cells were cultivated for 24 to 48 hours in a medium in which 531 compound was dissolved, and 531 was incorporated into the cells.
After confirming that a sufficient number of cells adhered to the medium, the plate was irradiated with parametric monochromatic X-rays or white X-rays. After irradiation, the cells were cultured for an arbitrary period of 24 hours or longer, and then the cells were peeled off with trypsin and stained with trypan blue to count only living cells.

  In addition, cells were seeded in a 10 cm diameter culture dish (dish), and cultured in a medium in which 531 compound was dissolved for an arbitrary period of time, so that 531 was incorporated into the cells.

  After confirming that a sufficient number of cells adhered to the medium, the cells were peeled off with trypsin, and an arbitrary number of cells were suspended in a 2 ml tube together with the medium. The tube was irradiated with parametric monochromatic X-rays or white X-rays. After irradiation, the cells were seeded in a 6-well plate or the like, and after confirming that a sufficient number of cells adhered to the medium, they were removed with trypsin, stained with trypan blue, and only live cells were counted.

  Arbitrary cell numbers (100-1000 cells) were seeded in a 10 cm dish and cultured in a medium in which 531 and 717 were dissolved so as to have an arbitrary final concentration. When it was confirmed that the cells were engrafted, parametric monochromatic X-rays or white X-rays were irradiated.

  Thereafter, colony formation assay was performed when colony formation was confirmed.

Parametric X-ray irradiation method At the Institute for Electron Beam Research and Application (LEBRA) at the Institute of Quantum Science, Nihon University, an electron beam accelerated by a linear accelerator (LINAC) is converted into parametric X-rays (PXR, Parametric X). -ray) as a light source. The PXR was fabricated by utilizing the electromagnetic radiation phenomenon that occurs when charged particles with relativistic velocity are incident on a material with a periodic structure like a crystal. In PXR, the wavelength of the X-ray generated by the incident angle of the electron beam incident on the crystal is uniquely determined, so that an arbitrary X-ray wavelength can be selected in a wide wavelength range.

  In LEBRA, PXR was generated by irradiating a silicon (Si) single crystal with electrons accelerated to 100 MeV by a linear accelerator. LEBRA-PXR has a variable wavelength range of 5 to 36 KeV (2.48 to 0.344 mm) by always guiding a wavelength angle dependent X-ray beam to the same optical path, theoretically 22 Ti (K absorption edge: 4.965 KeV). ) To 55 Cs (K absorption edge: 35.968 KeV). Further, if L, M, N, and the absorption edge are used, higher elements can be analyzed.

  Since LEBRA-PXR has a micro-macro pulse structure by using an electron beam accelerated by LINAC, the actual irradiation time when X-rays are actually irradiated is about 1 / 100,000 of the shutter opening time. (For example, the exposure time is 60 minutes and the actual irradiation time is 36 milliseconds). Since the X-ray beam of LEBRA-PXR has an angular divergence of 1 / γ, the beam size at the X-ray extraction port 7 m downstream from the light source (approximately 0.5 mm (V) x 1 mm (H)) is 70 mm or more ( E = 17.5 keV) and can be irradiated without scanning the X-ray beam using a special optical element.

  In this experiment, irradiation was performed with an iodine K absorption edge of 33.17 KeV.

  The results are shown in FIGS.

  The results in Figures 1, 2, 4, and 5 were analyzed by Dunnett's multiple comparison. The results in FIG. 3 were analyzed by t-test.

  In FIG. 1, 5000 HeLa cells were seeded in a 96-well plate, and a group administered with 531 at a concentration of 3 μg / ml and a non-administered group (531 non-administered irradiation group) were prepared and cultured for 24 hours. Thereafter, 33.17 keV parametric X-rays, which are the K absorption edge of iodine element, were irradiated for 1 hour (actual irradiation time was 36 milliseconds). At this time, the 531 administration group was further divided into 2 groups (531 administration shielding group, 531 administration irradiation group) with or without shielding with an aluminum plate placed under the lead plate.

  After culturing for 24 hours after irradiation, the number of living cells was determined by directly measuring the absorbance of formazan at 450 nm using the novel tetrazolium salt WST-8, which produces highly sensitive water-soluble formazan by WST-8 assay. The number and the amount of formazan produced were measured from a linear proportional relationship.

  In FIG. 1, the bar graphs are the 531 administration shielded group, the 531 non-administered irradiation group, and the 531 administration irradiation group from the left. In the 531-administered irradiation group, the number of viable cells was significantly reduced by 12% compared to the 531-administered group (P = 0.985), and the number of viable cells decreased by 9% (P = 0.903) compared to the irradiation group not administered with 531.

  In FIG. 2, 5,000 HeLa cells were seeded in a 96-well plate, and a group administered with 531 at a concentration of 3 μg / ml and a non-administered group (531 non-administered irradiation group) were prepared and cultured for 24 hours. Thereafter, irradiation with 33.17 keV parametric X-rays, which are the K absorption edge of the iodine element, was performed for 1 hour. At this time, the 531 administration group was further divided into 2 groups (531 administration shielded group, with or without shielding with an aluminum plate placed under the lead plate). 531 administration irradiation group). After irradiation, the cells were cultured for 66 hours, stained with trypan blue, and the number of viable cells was counted under a microscope.

  In FIG. 2, the bar graphs are the 531 administration shielded group, the 531 non-administered irradiation group, and the 531 administration irradiation group from the left. In the 531-administered irradiation group, the number of viable cells decreased by 44% (P = 0.467) compared to the 531-administered shielded group (P = 0.467), and the number of viable cells decreased by 56% (P = 0.181).

  In FIG. 3, three groups of 10000 HeLa cells seeded in two 12-well plates and 531 were administered at a concentration of 0 μg / ml, 3 μg / ml, or 6 μg / ml in 4 random holes on each plate, respectively. Prepared and cultured for 48 hours. Thereafter, parametric X-rays of 33.17keV, the K absorption edge of iodine element, were irradiated to one of the prepared plates for one hour, and the other one was left at the irradiation position for one hour under the same irradiation conditions, but no irradiation was performed. It was. Thereafter, each plate was cultured for 48 hours, the number of viable cells was stained with trypan blue, and the number of viable cells was counted under a microscope.

In FIG. 3, the bar graphs are in order from the left.
531 non-irradiated non-irradiated group,
3 μg / ml 531 administration non-irradiated group,
6 μg / ml 531 administration non-irradiated group,
531 non-administered irradiation group,
Irradiation group administered with 3 μg / ml 531 and irradiation group administered with 6 μg / ml 531.

  When 531 is not administered, the number of living cells is reduced to 74% by irradiation (P = 0.121), 3 μg / ml When 531 is not administered, the number of living cells is reduced to 62% (P = 0.275), and 6 μg / ml 531 is not administered The number of viable cells was reduced to 50% by irradiation (P = 0.05). In other words, the number of living cells decreased in a concentration-dependent manner.

In FIG. 4, 10,000 HeLa cells were seeded in a 12-well plate, and 531 was added at a concentration of 6 μg / ml and cultured for 24 hours. After that, energy of 31.97 KeV lower by 1.2 Kev than the K absorption edge (33.17 keV) of iodine element and 34.37 KeV higher by 1.2 Kev are set at the center of the irradiation field, and PXR irradiation is applied to these two groups by 1 Done for hours. After irradiation, the cells were cultured for 48 hours, and the number of viable cells was stained with trypan blue. The number of viable cells was counted under a microscope and compared with the non-irradiated group.
As a result, the number of viable cells decreased by 27% (P = 0.543) in the group irradiated with 31.97 KeV compared to the non-irradiated group administered with 6 μg / ml 531 (P = 0.543), and the number of cells in the 34.37 KeV irradiated group decreased by 47% (P = 0.220). ).

  In FIG. 5, 40,000 T24 cells were seeded in a 6-well plate, 531 was prepared in a 6 μg / ml concentration administration group and a non-administration group (531 non-administration irradiation group), and these were cultured for 24 hours. Thereafter, parametric X-rays of 33.17 keV, which is the K absorption edge of the iodine element, were irradiated for 1 hour. At this time, the non-administration group was further divided into two groups (non-administration shield group and non-administration irradiation group) depending on whether or not the shield was placed with an aluminum plate under the lead plate. After irradiation, the cells were cultured for 72 hours, stained with trypan blue, and the number of viable cells was counted under a microscope.

  In FIG. 5, the bar graphs are a non-administration shield group, a non-administration irradiation group, and a 6 μg / ml 531 administration irradiation group from the left.

  In the non-administered irradiation group, the number of viable cells decreased by 42% (P = 0.520) compared to the non-administration shielded group, and in the irradiated group, the number of viable cells decreased by 84% (P = 0.440) by administration of 531.

Summarizing these results, an experiment in which 33.17 KeV PXR, which is the K absorption edge of iodine, was irradiated for 36 milliseconds, and a human cervix administered with a compound obtained by adding iodine to a porphyrin derivative was shown. Cancer cell lines and bladder cancer cell lines caused a significant decrease in the number of viable cells after 48 to 66 hours of culture after irradiation. Moreover, the tendency for the number of cells to decrease more strongly was recognized by becoming higher than the K shell absorption edge compared with 32 KeV.

  Therefore, the method of the present invention leads to a decrease in the number of cancer cells by a porphyrin derivative utilizing the vicinity of the absorption edge using low energy single wavelength X-rays, thereby reducing cell death of cancer cells. It has been shown that it can be very useful.

Cell growth inhibition test
<WST-8>
T24 cell line (human bladder cancer cell line human bladder transitional-cell carcinoma), MCF7 cell line (human breast cancer cell line human mammary gland adenocarcinoma), etc. were seeded at a cell number of 500 cells / well in a 96-well plate.

  After 24 hours of cell culture, it was confirmed that a sufficient number of cells adhered to the medium, and 531 compound, 717 compound, HPPH-Gd compound (compound of formula II where X is Gd) (Japanese Patent Application Laid-Open No. 2004-26828 (P2004-26828A)) ) Was dissolved so that the final concentration was 3 μg / ml.

Cell culture was performed for 24 hours, and the cells were taken up with these compounds. Then, the medium was replaced with a fresh medium without compound, 4MeV white X-ray (2Gy absorbed dose), MEVATRON M2 / 6740 (Toshiba Medical Systems Co., Tochigi, Japan) as a radiation source, or 33KeV White X-rays (2Gy absorbed dose) were irradiated using MBR-1520R-3 (Hitachi Medical Co., Tokyo, Japan) as a radiation source. After 72 hours, the number of viable cells was counted by WST-8 assay.
<Colony formation assay>
HeLa (human cervical cancer cell line human cervical adenocarcinoma), T24 cell line (human bladder cancer cell line human bladder transitional-cell carcinoma) and the like were seeded on a 12-well plate at a cell number of 5000 to 10,000 cells / well.

Cell culture was performed for 48 to 72 hours to confirm that a sufficient number of cells adhered to the medium, and a medium in which the 531 compound was dissolved was added to a final concentration of 3 to 6 μg / ml.
Cell culture was performed for 24 hours, and the cells were taken up with these compounds. After that, the medium was replaced with a fresh medium without compound, and irradiated with 33 KeV white X-ray (2-6 Gy absorbed dose) and MBR-1520R-3 (Hitachi Medical Co., Tokyo, Japan) as a radiation source. .

  Immediately after the irradiation, the cells were peeled off with trypsin, stained with trypan blue, and seeded with 1000 cells / plate in a 10 cm dish.

The colony formation assay was performed when the cell culture was confirmed for 7 to 17 days and colony formation was confirmed.
<Result>
The results are shown in FIGS.

  The cells to which 531, 717 or HPPH-Gd was added to the medium by X-ray irradiation showed a decrease in the number of colonies or the number of living cells.

Evaluation of viable cell count by colorimetric determination using the reducing color reagent WST-8 Reduced color reagent WST-8 [2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, Using 4-disulfophenyl) -2H-tetrazolium, monosodium salt], experiments were conducted as follows.
<Experimental method>
(i) Cells (T24) are seeded in a 96-well plate at 5000 cells / well.

  (ii) After 24 hours, the porphyrin derivative (717) was added to 3 μg / ml.

  (iii) After 24 hours, the medium was aspirated and irradiated with 5 Gy white X-rays.

(iv) After 48 hours, the number of viable cells was evaluated by WST-8.
<Result>
The results are shown in FIG.

  A significant decrease in the number of viable cells was confirmed in the group to which 717 was added as compared with the control group having only the medium.

  Therefore, it was shown that when the porphyrin derivative was irradiated with X-rays, a radiosensitizing effect was obtained.

Evaluation of cell viability by colony formation assay <Experimental method>
(i) Cells (T24) are seeded at 1000 cells / dish in a 10 cm dish.

  (ii) After 24 hours, the porphyrin derivative (717) was added to 3 μg / ml.

  (iii) After 24 hours, the medium was aspirated and irradiated with white X-rays.

(iv) Fix after 7-9 days and evaluate the number of colonies by Diff-Quick staining.
<Result>
The results are shown in FIG.

  A decrease in the survival rate was confirmed in the group to which 717 was added, compared to the control group of the medium alone and the medium to which DMSO was added (DMSO final concentration 0.1%). In T24, colonies were not formed by irradiation with a low dose of 2 Gy.

  Therefore, it was considered that proliferation ability was suppressed when the porphyrin derivative was irradiated with X-rays.

Measurement of active oxygen by fluorescent probe reagent Aminophenyl Fluorescein (APF)
Although APF has almost no fluorescence in neutral aqueous solution, when these probes react with active oxygen species having strong activity, fluorescein, which is a strong fluorescent compound, is produced, and an increase in fluorescence intensity is observed.

Therefore, the following experiment was conducted in order to investigate whether or not active oxygen was generated in the group irradiated with X-rays by adding the compound of the present invention.
<Experimental method>
(i) A medium was added to a 96-well plate, and a porphyrin derivative (HPPH-Gd, 717) and 0.1% DMSO were added to the medium at 3 μg / ml.

  (ii) Aminophenyl Fluorescein (APF) was added to 5 μM.

  (iii) Irradiate 5Gy white X-rays.

  (iv) Incubate at 37 ° C for 30 minutes in the dark.

(v) Emission measurement at excitation wavelength of 485 nm and fluorescence detection of 535 nm <Results>
The results are shown in FIG.

  In FIG. 11, the upper panel shows the amount of active oxygen produced for T24 cells and the lower panel for MCF cells.

  Compared to the control group of the medium containing T24 cells (MEM), the medium containing MCF7 cells (RPMI1640), and the medium supplemented with DMSO (DMSO final concentration 0.1%), in the group added 717 compound or HPPH-Gd to the medium As a result, an increase in light emission was confirmed.

  That is, it was confirmed that when a test group containing 717 or HPPH-Gd compound is irradiated with X-rays, active oxygen is generated.

  Therefore, it was considered that the radiosensitization effect of the porphyrin derivative was based on the generation of active oxygen.

  According to the present invention, photodynamic therapy using radiation and a compound used in the therapy are provided. According to the present invention, it is possible to perform diagnosis and treatment as a set using the same diagnostic drug compound together with conventional diagnosis of cancer. In addition, by performing surgery after irradiating tumor cells during surgery using a single wavelength of low energy, it is possible to provide a therapeutic method capable of preventing the remaining of the tumor cells and the recurrence of cancer.

Claims (11)

Formula I:
Wherein R ¹ , R ⁴ , R ⁷ and R ¹⁰ are each independently a hydrogen atom, an oxygen atom, an optionally substituted C _1-10 alkyl, or an optionally substituted C _{2 Represents -10} alkenyl, optionally substituted C _2-10 alkynyl, optionally substituted C _6-14 aryl or optionally substituted 5-14 membered heteroaryl, wherein The group is an oxygen atom, C _1-6 alkyl, and at least one selected from the group consisting of OR ²⁰ and COOR ²⁰ (R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl). And
R ² , R ⁵ , R ⁸ and R ¹¹ are each independently a hydrogen atom, an oxygen atom, an optionally substituted C _1-10 alkyl, an optionally substituted C _2-10 alkenyl, Represents optionally substituted C _2-10 alkynyl, optionally substituted C _6-14 aryl or optionally substituted 5-14 membered heteroaryl, wherein the substituent is oxygen Atoms, C _1-6 alkyl, and OR ³⁰ and COOR ³⁰ (R ³⁰ is a hydrogen atom, optionally substituted C _1-6 alkyl, optionally substituted C _2-10 alkenyl, optionally Represents an optionally substituted C _6-14 aryl, an optionally substituted C _7-20 arylalkyl or an optionally substituted 5-14 membered heteroaryl, each substituent having a K-shell absorption edge Group may be further substituted with one or more of the elements after element number 15 (P) showing 2 KeV or more. At least one selected et al.,
R ³ , R ⁶ , R ⁹ and R ¹² are each independently a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _6-14 aryl, C _7-20 aryl Represents alkyl, 5-14 membered heteroaryl, C _1-10 alkoxy, C _2-10 alkenyloxy, C _2-10 alkynyloxy, C _6-14 aryloxy or 5-14 membered heteroaryloxy, said alkyl, alkenyl , Alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy and heteroaryloxy are, optionally, C _1-6 alkyl, C _6-14 aryl, C _7-20 arylalkyl,- (CH ₂ CH ₂ O) _n -R ²⁰ ,-(CH ₂ ) _n -OR ²⁰ and-(CH ₂ ) _n -COOR ²⁰ (n is an integer of 0 to 6, and R ²⁰ is the same as above. And one of the elements after element number 15 (P) indicating that the K-shell absorption edge is 2 KeV or more. May be substituted with at least one member selected from the group consisting of a plurality, each substituent, C _1-6 alkyl, C _2-6 alkenyl, or K-shell absorption edge element number 15 that indicates the above 2 KeV (P ) May be further substituted with one or more of the following elements,
R ⁸ and R ⁹ can form a saturated or unsaturated 5-membered ring or 6-membered ring, and the ring is optionally an oxygen atom, C _1-6 alkyl and COOR ²⁰ (R ²⁰ is And may be substituted with at least one selected from the group consisting of:
M is a metal, silicon or hydrogen atom, the metal is Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, In, Sn, Sb, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Ac, Th, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No and Selected from Lr,
Represents a single bond or a double bond. )
An antitumor agent comprising the porphyrin compound, wherein the porphyrin compound is used to irradiate radiation when accumulated in a tumor tissue of a mammal. R ¹ , R ⁴ , R ⁷ and R ¹⁰ each independently represent a hydrogen atom or an optionally substituted C _1-10 alkyl, wherein the substituent is an oxygen atom, C _{1- 6. The} alkyl group according to claim 1, which is at least one selected from the group consisting of ₆ alkyl, and OR ²⁰ and COOR ²⁰ (R ²⁰ represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl). Antitumor agent. R ² , R ⁵ , R ⁸ and R ¹¹ each independently represent a hydrogen atom or an optionally substituted C _1-10 alkyl, wherein the substituent is an oxygen atom, C _{1- 6} alkyl, and OR ³⁰ and COOR ³⁰ (R ³⁰ represents a hydrogen atom, an optionally substituted C _1-6 alkyl, or an optionally substituted C _6-14 aryl. The K-shell absorption edge may be further substituted with one or more of the elements after element number 15 (P) showing 2 KeV or more.), At least one selected from the group consisting of Or the antitumor agent of 2. R ³ , R ⁶ , R ⁹ and R ¹² are each independently a hydrogen atom, optionally substituted C _1-10 alkyl, optionally substituted C _6-14 aryl, optionally substituted Represents optionally substituted C _6-14 aryloxy, or optionally substituted 5-14 membered heteroaryl, wherein each substituent is optionally C _1-6 alkyl, C _6-14 aryl, C _{7 -20} arylalkyl,-(CH ₂ CH ₂ O) _n -R ²⁰ ,-(CH ₂ ) _n -OR ²⁰ and-(CH ₂ ) _n -COOR ²⁰ (n is an integer from 0 to 6, R ²⁰ Represents a hydrogen atom, C _1-6 alkyl or C _2-6 alkenyl.), And a group consisting of one or more of the elements after element number 15 (P) whose K-shell absorption edge is 2 KeV or more. At least one selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, or an element of element number 15 (P) on which the K-shell absorption edge indicates 2 KeV or more. One or more of them It may be further substituted, antitumor agent according to any one of claims 1 to 3. R ⁸ and R ⁹ can form a saturated or unsaturated 5-membered ring or 6-membered ring, and the ring is optionally an oxygen atom, C _1-6 alkyl and COOR ²⁰ (R ²⁰ is hydrogen The antitumor agent according to any one of claims 1 to 4, which may be substituted with at least one selected from the group consisting of an atom, C _1-6 alkyl or C _2-6 alkenyl. The porphyrin compound is one containing C _6-14 aryl or C _7-20 arylalkyl substituted with one or more of the elements after element number 15 (P) showing a K-shell absorption edge of 2 KeV or more. Item 6. The antitumor agent according to any one of Items 1 to 5.   The element after element number 15 (P) having a K-shell absorption edge of 2 KeV or more is selected from halogen, lanthanoid, Y, Tc, Ru, Ba, In, Cs, Pt, Au and Tl. The antitumor agent of any one of -4.   The antitumor agent according to claim 7, wherein the halogen is I or Br. The porphyrin compound is represented by any one of the following formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and XVI. Antitumor agent.
  The antitumor agent according to any one of claims 1 to 9, wherein the radiation is parametric monochromatic X-rays. Porphyrin compounds represented by the following formulas IV, IX, XIII, XIV, XV or XVI.