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    • 专利摘要:
    The effective treatment of tumors, particularly cancer, is achieved by administering to a human a photochemotherapeutic agent containing, as an active ingredient, a compound exhibiting maximum absorption in the wavelength range of 800 to 1200 nm, followed by irradiation with a light beam having a wavelength of 800 to 1200 nm .
    公开号:KR20010075107A
    申请号:KR1020017003304
    申请日:1999-09-16
    公开日:2001-08-09
    发明作者:에키모토히사오；오니시마사오；세노지에코；사카이데루유키
    申请人:다께다 가즈히꼬；니폰 가야꾸 가부시끼가이샤；
    IPC主号:
    专利说明:

    Photochemical Therapeutics {REMEDIES FOR PHOTOCHEMOTHERAPY}
    [2] Currently, photochemotherapy has been put to practical use as an effective therapy for tumors such as cancer. Research on photochemotherapy started relatively early, and its clinical application was put into practical use in early 1976. A lot of literature and patents have been published on this subject, one example being Michael J. Manya et al. (J. Clin. Oncology, 6, 380, 1988). According to these documents and patents, compounds which have been studied so far and which have been clinically applied as photochemotherapeutic agents are mostly porphyrin compounds, and Dihematoporphyrin is commercially available from Nippon Lederle under the trade name Photofrin In Japan.
    [3] Hereinafter, photochemical therapy using such a porphyrin compound will be described.
    [4] When the drug is administered to a cancer patient (in the case of excluding the surgical treatment, the kind of cancer to which the therapy is applied is limited to cancer in a region adjacent to the body surface such as skin cancer in principle) Within a few days, it is metabolized in normal cells, while the drug ingested by cancer cells remains in the cells. The amount of the drug remaining in the cancer cells is several times to several tens of times that of the normal cells. When irradiated with cancer light at a wavelength of 600 to 700 nm, only those cells that retain the drug specifically die, whereas normal cells remain unaffected. The reason why the drug remains only in cancer cells has not yet been clarified. However, this phenomenon is caused by the difference in the blood circulation state between normal cells and cancer cells, or due to the difference in the activity of the immune system such as lymphoid cells I think there is. The reason why the cancer-retaining drug cells are killed by the irradiation of light is not clearly understood, but it is considered that the surrounding oxygen is converted into a singlet having a stronger toxicity by the energy transfer from the drug activated by light irradiation ) And oxygen.
    [5] However, photochemical therapy using the porphyrin compound has some problems. One problem exists in the relationship between the absorption wavelength of the compound itself and the wavelength of light used for treatment. The wavelength of the light used for treatment is preferably 600 nm or more, which is not absorbed or scattered by the substances in the living body, and does not affect the hemoglobin of red blood cells. However, the absorption of light by the above-mentioned Photofrin, which is commercially available as dihematoporphyrin in the wavelength region of 600 nm or more, is only 2 to 3% at the maximum absorption wavelength of 363 nm of this compound. Therefore, there is no alternative to photochemotherapy which is practically ineffective, and it is necessary to increase the dose of the drug or to increase the dose of the drug, so that the side effects are increased or the cost .
    [6] Another problem is the phototoxicity of porphyrin-based compounds to the skin, such that the drug-treated patient must live to avoid being exposed to sunlight for about 6 to 8 weeks. Another problem is that the range of treatment is limited because the light in the wavelength region around 630 nm penetrates only a few millimeters into the tissue. This is an obstacle in the clinical application of the above compounds.
    [1] The present invention relates to a therapeutic agent for photochemotherapy which is effective, for example, in the treatment of tumors, particularly cancer.
    [7] SUMMARY OF THE INVENTION [0006] The present invention is directed to provide a completely new type of phototherapeutic agent for solving the conventional problems.
    [8] The inventors of the present invention have discovered a therapeutic agent for photochemotherapy which has an extremely high tissue permeability and a strong absorptivity in a functional dye, thereby completing the present invention. That is, the present invention relates to the following contents (1) to (30).
    [9] (1) A photochemical therapeutic agent containing a compound exhibiting maximum absorption at a wavelength of 800 to 1200 nm as an active ingredient.
    [10] (2) A photochemotherapeutic agent containing a diimonium type compound exhibiting maximum absorption in a wavelength region of 800 to 1200 nm as an active ingredient.
    [11] (3) The photomedical therapeutic agent according to (2), wherein the diimonium type compound is a compound having a skeleton structure represented by the following structural formula (12).
    [12]
    [13] (4) The photomedical therapeutic agent according to (2), wherein the diimonium type compound is a compound represented by the following structural formula (3) or a pharmacologically acceptable salt thereof.
    [14]
    [15] Wherein R 1 to R 8 independently represent a C1 to C12 substituent, X represents an anion, n is a number of 1 or 2, the ring A and the four rings B independently of one another are each substituted with 1 to 4 substituents .
    [16] (5) The therapeutic agent for chemotherapy according to (4), wherein each of R 1 to R 8 is a hydrophobic group.
    [17] (6) The therapeutic agent for photochemotherapy according to (4), wherein R 1 to R 8 are each a C 1 to C 5 alkyl group, and ring A and four rings B have no substituent.
    [18] (7) A photochemotherapeutic agent containing, as an active ingredient, an aminium type compound exhibiting maximum absorption in a wavelength region of 800 to 1200 nm.
    [19] (8) The photochemical therapy agent according to (7), wherein the aminium type compound is a compound having a skeleton structure represented by the following structural formula (13).
    [20]
    [21] In the above formula, m is a number of 1 or 2.
    [22] (9) The photochemotherapeutic agent according to (7), wherein the aminium type compound is a compound represented by the following structural formula (4) or a pharmacologically acceptable salt thereof.
    [23]
    [24] Wherein R 1 to R 8 independently represent a C1 to C12 substituent, X represents an anion, n is a number of 1 or 1/2, m is a number of 1 or 2, and one or two rings A and / The four rings B may independently have 1 to 4 substituents each independently of each other.
    [25] (10) The photochemical therapeutic agent according to (9), wherein R 1 to R 8 are each a hydrophobic group.
    [26] (11) The therapeutic agent for photochemotherapy according to (9), wherein R 1 to R 8 are each a C 1 to C 5 alkyl group, m is 1, and Ring A and 4 rings B have no substituent.
    [27] (12) A photochemotherapeutic agent according to (1), wherein the compound is a naphthalocyanine type compound or an anthracenium type compound.
    [28] (13) The photochemotherapeutic agent according to (12) above, wherein the compound is a compound represented by the following structural formula (1) or (2) or a pharmacologically acceptable salt thereof.
    [29]
    [30]
    [31] Wherein X represents an oxygen atom, a sulfur atom, NH, SO 2 , CO or a single bond; R 1 represents an optionally substituted aryl, aralkyl or alkyl group, an alkoxyl group, an alkylamino group or a hydroxyl group; k, l, m and n each represent an integer of 0 to 4; when k + 1 + m + n is 2 or more, R 1 and X may be the same or different; M represents one kind of a ligand such as a halogen atom, a hydroxyl group, an aryloxy group, an alkoxyl group, a trialkylsiloxy group, a triarylsiloxy group, a trialkoxysiloxy group, a triaryloxysiloxy group, Or a metal oxide or a metal which may be present in an amount sufficient to overcome the above problems.
    [32] (14) The photochemotherapeutic agent according to (1), wherein the compound is a complex or a pharmacologically acceptable salt thereof represented by the following structural formula (5).
    [33]
    [34] Wherein R 1 to R 4 independently represent a hydrogen atom or an optionally substituted alkyl, aryl, alkylthio or arylthio group, or R 1 and R 2 and / or R 3 and R 4 bond to each other to form a substituent And M represents Ni, Pd, Co, VO, Cu or Pt.
    [35] (15) The therapeutic agent for photochemotherapy according to (1), wherein the compound is a bissquarilium type compound.
    [36] (16) The photochemotherapeutic agent according to (15), wherein the compound is a compound represented by the following structural formula (6) or a pharmacologically acceptable salt thereof.
    [37]
    [38] In the above formula, Ring A and Ring B independently represent a heterocycle having a nitrogen atom, and X represents a benzene ring substituted by a group of the following structural formula or an alkylamino group.
    [39]
    [40] (In the above formula, ring C represents a heterocycle having a nitrogen atom.)
    [41] (17) The photochemotherapeutic agent according to (1) above, wherein the compound is a metal-containing indoaniline type compound.
    [42] (18) The photochemotherapeutic agent according to (17) above, wherein the compound is a compound represented by the following structural formula (7) or a pharmacologically acceptable salt thereof.
    [43]
    [44] In the above formula, M represents a chelated metal ion; R 1 represents a hydrogen atom, an optionally substituted alkyl, aryl, arylalkyl, alkoxyl, alkylamino or alkylaminocarbonyl group, a halogen atom, a hydroxyl group, an amino group, an acylamino group, a sulfonylamino group, an aminocarbonyl group or a nitro group; R 2 and R 3 independently represent a halogen atom or a monovalent organic group; X is a group represented by the following structural formula,
    [45]
    [46] -OR 6 or a hydroxyl group; Z - represents an anion; R 4 , R 5 and R 6 independently represent an optionally substituted alkyl group; m and n are each an integer of 0 to 3, and when m and n are each 2 or more, R 2 and R 3 may be the same or different.
    [47] (19) The pharmaceutical composition according to the above (1), wherein the compound is selected from the group consisting of polymethine or other types of compounds represented by any one of the following structural formulas (8) to (11) Photochemotherapeutic agents that are acceptable salts.
    [48]
    [49]
    [50]
    [51] R 1 to R 7 independently represent a monovalent organic group such as a hydrogen atom, a halogen atom, an optionally substituted alkyl group, a hydroxyl group, an optionally substituted alkoxyl group or an amino group, a saturated alicyclic group, an unsaturated alicyclic group, R 1 to R 3 , R 2 to R 4 , R 3 to R 5 , R 4 to R 6, and R 5 to R 6 represent a substituted or unsubstituted aromatic group, a saturated heterocyclic group, an aromatic group, a heteroaromatic group, 7 may form a ring which may be a 5-membered, 6-membered or 7-membered substituted or unsubstituted saturated alicyclic ring, an unsaturated alicyclic ring, a saturated heterocyclic ring or an aromatic ring, a heteroaromatic ring or condensed ring thereof, ;
    [52] A to D independently of one another are a hydrogen atom, an optionally substituted aromatic ring, a heteroaromatic ring, a substituent represented by any one of the following structural formulas
    [53]
    [54] (Wherein the substituted or unsubstituted condensed ring is ROne~ R2, R2~ R3, R3~ R4, R5~ R6And R6~ R7, Or a group having a heteroatom in the azulene skeleton, provided that at least two of A to D are not hydrogen atoms at the same time; ROne~ R7Is selected from the above monovalent organic moieties, R14 And R15Is selected from the above-mentioned monovalent organic moieties and optionally substituted phenyl groups; A-B and C-D may form a ring to form a group represented by the following formula
    [55]
    [56] [Wherein R 8 and R 9 independently represent an aromatic ring, a styryl group or a heteroaromatic ring group which may be substituted with a monovalent organic residue such as a halogen atom, an alkyl group, a hydroxyl group, an alkoxyl group or an amino group; And X represents a hetero atom such as oxygen, sulfur, selenium or tellurium atom, or represents a substituted nitrogen atom or the following structural formula.
    [57]
    [58] (Wherein Y represents a hetero atom such as oxygen, sulfur, selenium or tellurium atom, a substituted or unsubstituted methylene group or a substituted nitrogen atom, and R 1 to R 7 are selected from the above-mentioned monovalent organic residue) ];
    [59] X represents an anion.
    [60] (20) The therapeutic agent for photochemotherapy according to (1) above, wherein the compound has a radical in the molecule.
    [61] (21) A phototherapeutic therapeutic agent according to any one of (1) to (20) above, which contains a pharmacologically acceptable carrier.
    [62] (22) The photochemotherapeutic agent according to (21) above, wherein the pharmacologically acceptable carrier is a solvent.
    [63] (23) The therapeutic agent for photochemotherapy according to (22), wherein the compound according to any one of (1) to (20) is contained at a concentration of 0.1 to 100 mg / ml.
    [64] (24) The photochemical therapeutic agent according to (22) or (23), wherein the solvent is physiological saline, a 5% glucose solution or a mannitol solution.
    [65] (25) The photochemotherapeutic agent according to (22) or (23), wherein the solvent is a water-soluble organic solvent such as glycerol, ethanol, dimethylsulfoxide, polyethylene glycol or Cremophor.
    [66] (26) The photochemical therapeutic agent according to (22) or (23), wherein the solvent is a mixture of water and a water-soluble organic solvent.
    [67] (27) The photochemotherapeutic agent according to (25) or (26), wherein the water-soluble organic solvent is dimethylsulfoxide or ethanol.
    [68] (28) A photochemical therapy method of tumor comprising irradiating a light beam having a wavelength in the range of 800 to 1200 nm after administration of the photochemical therapeutic agent according to any one of (1) to (27) above.
    [69] (29) The phototherapeutic treatment method according to (28), wherein the administration is carried out by applying a therapeutic agent for photochemotherapy to the surface of the tumor or directly injecting a therapeutic agent for photochemotherapy into the tumor.
    [70] (30) The photochemical therapy method according to (28), wherein the light beam is a laser beam.
    [71] Hereinafter, the present invention will be described in detail.
    [72] The compounds which exhibit the maximum absorption in the 800 to 1,200 nm wavelength range which can be used as the active ingredient of the photochemotherapeutic agent of the present invention are not limited. For example, naphthalocyanine type compounds, anthracenium type compounds, diimonium type compounds, particularly those having a skeleton structure represented by the structural formula (12), aminium type compounds, particularly those having a skeleton structure represented by the structural formula (13) , A bisquirium type compound, a metal containing indoaniline type compound, a polymethine type compound, a cyanine type compound, an azocene type compound, and various kinds of complex compounds may be used, but any one of the structural formulas (1) to The compounds represented or pharmacologically acceptable salts thereof are preferred. In particular, a diimonium type compound having a skeleton structure represented by the structural formula (12), an aminium type compound having a skeleton structure represented by the structural formula (13), and a compound represented by any one of structural formulas (1) Or pharmacologically acceptable salts thereof which exhibit maximum absorption in the 930 to 1100 nm wavelength region are preferred.
    [73] In the structural formulas (12) and (13), when the nitrogen atom is bonded to the 1-position, the substituted amino group may be bonded to 4 positions of each of the 4 phenyl groups. The molecular extinction coefficient ( ) At the maximum absorption wavelength of the compounds used in the present invention is preferably 5 × 10 3 or more, more preferably 1 × 10 4 or more, particularly 2 × 10 4 or more.
    [74] Hereinafter, each of the compounds of the structural formulas (1) to (11) will be described in detail.
    [75] i) Compounds of structural formulas (1) and (2)
    [76] Examples of the optionally substituted aryl group include an alkyl group having 1 to 15 carbon atoms, more preferably 1 to 10 carbon atoms, an alkoxyl group having 1 to 15 carbon atoms, more preferably 1 to 10 carbon atoms, A naphthyl group and a heteroaromatic compound residue which may have a substituent (s) of the formula (I). Examples of these groups include alkyl-substituted phenyl or naphthyl groups such as phenyl, 4-methylphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 4- Naphthyl groups), alkoxy and / or alkylthio-substituted phenyl or naphthyl groups (such as 4-methoxyphenyl, 4-butoxyphenyl, 4-octyloxyphenyl and 4-ethylthiophenyl groups) Aromatic ring compound residues (e.g., gamma-pyridyl and 8-quinolyl groups).
    [77] Examples of the optionally substituted aralkyl group include an alkyl group having 1 to 15 carbon atoms, preferably 1 to 3 carbon atoms, and an alkoxyl group having 1 to 5 carbon atoms, more preferably 1 to 3 carbon atoms, ), And a benzyl group and a phenylethyl group. Practical examples of these groups are benzyl, 2-phenylethyl, (4-methylphenyl) methyl and (4-ethoxyphenyl) methyl. Examples of the optionally substituted alkyl group include a straight chain alkyl group (e.g., methyl, ethyl, n-propyl, n-butyl, n-hexyl, -Butyl, tert-pentyl, neopentyl and 2-methylpentyl groups). The alkyl group of these alkyl groups preferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. These alkyl groups may have a substituent such as a halogen atom, an amino group, a hydroxyl group, a cyano group, a carboxyl group, a sulfone group and a group of the following structural formula.
    [78]
    [79] (Wherein R 2 represents a C 2 -C 3 alkylene group, R 3 represents a C 1 -C 10 alkyl group, preferably a C 1 -C 6 alkyl group, and p is an integer of 0 to 10, preferably an integer of 0 to 6 .) The alkyl group in the optionally substituted alkoxyl group is the same as the above-mentioned optionally substituted alkyl group. Furthermore, the alkyl group in the optionally substituted alkylamino group is the same as the above-mentioned optionally substituted alkyl group. These alkyl groups may be mono-form or di-form, and in the latter case, the alkyl groups may be the same or different.
    [80] k, l, m and n each represent an integer of 0 to 4, preferably an integer of 1 to 2. k + l + m + n is an integer of 1 or more, preferably an integer of 4 to 8.
    [81] The metal represented by M includes Cu, Ni, Mg, Pb, V, Si, Pd, Co, Nb, Al, Sn, Zn, Ca, In, Ga, Fe and Ge. Among these metals, Cu, Ni, Mg, Zn, V, Co and Si are preferable.
    [82] Examples of halogen atoms which may be coordinated to M include F, Cl and Br. Among the groups that may be coordinated to M, examples of the aryl group include phenyl and alkoxyl groups such as those having 1 to 6 carbon atoms, alkyl groups having 1 to 6 carbon atoms, and acyl groups having 1 to 6 carbon atoms, for example. When the halogen or the group mentioned above is coordinated to M, the number of coordination is usually 1 to 2.
    [83] ii) The compound of formula (3)
    [84] R 1 to R 8 and X which are substituents which may be present on ring A or B are the same groups as the substituents of the compounds of formula (4) described below.
    [85] In addition, preferable substituents represented by R 1 to R 8 are the same groups as the substituents of the compounds of the structural formula (4) described below.
    [86] N is 2 when X is a monovalent anion, and n is 1 when X is a divalent anion.
    [87] iii) Compound of formula (4)
    [88] Ring A and each ring B may or may not have 1 to 4 substituents. Examples of the substituent bonded to these rings include a halogen atom, a hydroxyl group, an alkoxyl group, a cyano group and a lower alkyl group. The halogen atom is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. As the alkoxyl group, a C1-C5 alkoxyl group such as methoxy group or ethoxy group is used. As the lower alkyl group, a C1-C5 alkyl group such as methyl group or ethyl group is used. It is preferable that Ring A is substituted with no substituent or with a halogen atom (especially chlorine atom or bromine atom), methyl group or cyano group. Each ring B preferably has no substituent at all.
    [89] Examples of the C1-C12 substituent represented by R 1 to R 8 in the above structural formula include a hydrophobic group. Specific examples thereof include an alkyl group, an alkoxyalkyl group, an alkenyl group, an aralkyl group, and an alkynyl group. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, . Of these alkyl groups, those having 1 to 5 carbon atoms are preferred. Examples of the alkoxyalkyl group include (C1-C4) alkoxy (C1-C4) alkyl groups such as methoxyethyl, ethoxyethyl and methoxypropyl groups. Examples of the alkenyl group include vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl groups. An alkenyl group having 1 to 5 carbon atoms is preferred. Examples of the aralkyl group include a phenyl (C1-C4) alkyl group (e.g., benzyl group, p-chlorobenzyl group, p-methylbenzyl group, 2-phenylethyl group, 2-phenylpropyl group, C4) alkyl group (for example, -Naphthylmethyl group and -Naphthylmethyl group). Examples of the alkynyl group include C1-C5 alkynyl groups such as propargyl, butynyl, pentynyl and hexynyl. Among these groups, an alkyl group having 1 to 5 carbon atoms is preferable.
    [90] X represents a monovalent or divalent anion. When this is a monovalent anion, n is 1, and when it is a divalent anion, n is 1/2. Examples of the monovalent anion represented by X include an organic acid monovalent anion and an inorganic monovalent anion. Examples of the organic acid monovalent anion include organic carboxylate ions such as acetate ion, lactate ion, trifluoroacetate ion, propionate ion, benzoate ion, oxalate ion, succinate ion and stearate ion, A sulfonate ion such as sodium ion, toluene sulfonate ion, naphthalene monosulfonate ion, chlorobenzene sulfonate ion, nitrobenzenesulfonate ion, dodecylbenzenesulfonate ion, benzenesulfonate ion, ethanesulfonate ion and trifluoromethanesulfonate And organic borate ions such as tetraphenylborate ion and butyltriphenylborate ion. A halogenoalkylsulfonate ion such as a trifluoromethanesulfonate ion and a toluenesulfonate ion or an alkylarylsulfonate ion is preferable.
    [91] Examples of the inorganic monovalent anion include a halogen ion such as a fluorine ion, a chlorine ion, a bromine ion, and an iodine ion, a thiocyanate ion, a hexafluoroantimonate ion, a perchlorate ion, a periodate ion, a nitrite ion, a tetrafluoroborate Ion, a hexafluorophosphonate ion, a molybdate ion, a tungstate ion, a titanate ion, a vanadate ion, a phosphonate ion, and a borate ion. Among these inorganic monovalent anions, perchlorate ion, iodate ion, tetrafluoroborate ion, hexafluorophosphonate ion and hexafluoroantimonate ion are preferable.
    [92] Examples of divalent anions include naphthalene disulfonic acid derivatives such as naphthalene-1,5-disulfonic acid, R-acid, G-acid, H-acid, benzoyl H-acid, p- Acid, c-acid, epsilon-acid, p-toluenesulfonyl R-acid, naphthalene-1-acetic acid, Disulfonic acid, and 1-naphthol-4,8-disulfonic acid with an ion of a divalent organic acid such as carbonyl J-acid, 4,4'-diaminostilbene-2,2'-disulfonic acid, Naphthalene-2,3-dicarboxylic acid, diphenic acid, stilbene-4,4'-dicarboxylic acid, 6-sulfo-2-oxy-3-naphthoic acid, anthraquinone Disulfonic acid, 1,6-diamino anthraquinone-2,7-disulfonic acid, 2- (4-sulfophenyl) -6-aminobenzotriazole- -5-pyrazolonyl) -naphthalene-1,3-disulfonic acid, and 1-naphthol-6- (4-amino-3-sulfo) anilino-3-sulfonic acid.
    [93] Preferable examples of these anions include chloride ion, bromide ion, perchlorate ion, iodide ion, tetrafluoroborate ion, hexafluorophosphonate ion, hexafluoroantimonate ion, trifluoromethanesulfonate ion, and toluenesulfonate Ions.
    [94] iv) Compound of formula (5)
    [95] As the alkyl group, those having 1 to 10 carbon atoms, especially 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl and the like are preferable. Examples of the aryl group include a phenyl group and a naphthyl group. As the alkylthio group, those having 1 to 10 carbon atoms, particularly 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio and the like are preferable. Examples of the arylthio groups include a phenylthio group and a naphthylthio group.
    [96] These alkyl, aryl, alkylthio and arylthio groups may have substituent (s). Examples of such a substituent include a halogen atom (fluorine atom, chlorine atom and bromine atom), a C1-C6 alkylamino or dialkylamino group, a C1-C6 alkoxyl group, a C1-C6 acyl group and a C1- The number is preferably 1 to 5.
    [97] When R 1 and R 2 , and / or R 3 and R 4 are combined to form a ring, such a ring is, for example, a C5-C7 aromatic ring or a heterocyclic ring. The above substituent (s) may be present in the ring.
    [98] M may be charged, and the compound of formula (5) may take a salt structure with a cation.
    [99] v) Compound of formula (6)
    [100] Representative examples of rings A, B and C include a nitrogen-containing condensed ring of the following structural formula.
    [101]
    [102] In the structural formula, the rings A, B and C may be the same or different. Rings D, E and F may be benzene rings or naphthalene rings which may have substituent (s) independently of each other. Preferred examples of such substituents include lower alkyl groups such as methyl and ethyl groups, lower alkoxyl groups such as methoxy and ethoxy groups, halogen atoms such as chlorine atom and bromine atom such as perfluoroalkyl groups such as trifluoromethyl group and pentafluoro group, Ethyl group), a sulfonic acid group, a carboxylic acid group, a hydroxyl group and a phosphoric acid group. Two or more of these substituents may be bonded.
    [103] R 1 , R 4 and R 5 may be, for example, an alkyl group which may have a substituent (s). Examples of such alkyl groups include C1-C8 unsubstituted alkyl groups such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and n-octyl groups; An alkyl group having 1 to 4 ether groups such as methoxyethyl, ethoxyethyl, methoxypropyl and methoxyethoxyethoxyethyl groups; An alkyl group substituted with an aryl group such as an optionally substituted phenyl group, such as a phenylethyl group or a phenylpropyl group; An alkyl group substituted with an aryloxy group such as an optionally substituted phenoxy group, such as a phenoxyethyl group, a phenoxypropyl group; An alkyl group substituted with a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom; A thioamide group, a hydroxyl group, a thiol group, a carboxylic acid ester group, a sulfone group, a furyl group, a thioether group, a thioether group, an ester group, a cyano group, a nitro group, a thioether group, a carbonyl group, a sulfonyl group, And other alkyl groups having a substituent group such as a tetrahydrofuryl group.
    [104] R 2 and R 3 each represent an alkyl group. They may be bonded to each other to form a ring. Examples of the alkyl group represented by R 2 and R 3 are lower alkyl groups such as methyl, ethyl, propyl and butyl groups. Examples of the ring formed by R 2 and R 3 include an aliphatic hydrocarbon ring such as cyclopentane ring, cyclohexane ring, and cycloheptane ring, or a bridged structure such as norbornane ring, adamantane ring, and bicyclo [3.3.1] A good hydrocarbon ring may be mentioned.
    [105] Examples of the benzene ring substituted with an alkylamino group of X include those represented by the following structural formulas.
    [106]
    [107] In the above formula, R 6 and R 7 may be the same alkyl groups as those denoted by R 1 , R 4 and R 5 . The alkyl group of R 6 and R 7 may be bonded together with the phenyl group to form a nitrogen-containing 5-membered ring, a 6-membered ring or a 7-membered ring, or may further form a condensed ring with a phenyl group.
    [108] R 8 and R 9 each represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxyl group or an acylamino group. Examples of the optionally substituted alkyl group represented by R 8 and R 9 include an unsubstituted C 1 -C 8 alkyl group such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and n-octyl groups and methoxyethyl, , Methoxypropyl, and methoxyethoxyethoxyethyl groups, and alkyl groups having 1 to 4 ether groups. Examples of the optionally substituted alkoxyl group include unsubstituted C1-C8 alkoxyl groups such as methoxy, ethoxy, n-propyloxy, n-butyloxy, n-hexyloxy and n-octyloxy groups; And alkoxyl groups having 1 to 4 ether groups, such as methoxyethoxy, ethoxyethoxy, methoxypropyloxy and methoxyethoxyethoxyethoxy groups. Examples of the acylamino group include an alkylcarbonylamino group such as an acetylamino group and a propionylamino group.
    [109] vi) Compound of formula (7)
    [110] M represents a chelating metal ion such as nickel ion, copper ion, cobalt ion, iron ion and zinc ion, and nickel ions and copper ions are preferable.
    [111] Examples of the substituent of the alkyl, aryl, arylalkyl, alkoxyl, alkylamino and alkylaminocarbonyl groups represented by R 1 include a halogen atom (fluorine atom, chlorine atom and the like), an alkyl group, an aryl group, a heterocyclic group, a nitro group, A sulfonyl group, an acylamino group, a carbamoyl group, a sulfonyl group, a sulfonyl group, a hydroxyl group, a carboxyl group, an amino group, and a primary And a secondary amino group.
    [112] As the alkyl group, straight chain or branched alkyl groups having a carbon atom preferably having 1 to 8, more preferably 1 to 6, such as methyl, ethyl, propyl, butyl and octyl groups are exemplified. As the aryl group, a phenyl group is preferable.
    [113] Examples of the alkoxyl group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and isobutoxy groups. Examples of the alkylaminocarbonyl group include N-methylaminocarbonyl, N-ethylaminocarbonyl, N-propylaminocarbonyl, N-isopropylaminocarbonyl, N-butylaminocarbonyl, N-isobutylaminocarbonyl, Dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N, Nn-dipropylaminocarbonyl, N, N-iso-dipropylaminocarbonyl, N, , And N-isodibutylaminocarbonyl group. Examples of the acylamino group include acetylamino, propionylamino and benzoylamino groups.
    [114] R 2 and R 3 represent a halogen atom or a monovalent organic group. The halogen atom is preferably a chlorine atom or a fluorine atom. Monovalent organic group is an optionally substituted alkyl (C1-C10 alkoxy group such as methoxy group and ethoxy group), (methyl group, and C1-C8 alkyl group and the like), an optionally substituted alkoxyl group, -CONR 7 R 8, -NHCOR 9 , -NHCO 2 R 9 , -NHSO 2 R 9 , -NHSO 2 NR 7 R 8 , -COOR 9 , -SO 2 R 9 , -NHCONR 7 R 8 and cyano group. In the above formulas, R 7 and R 8 each represent a hydrogen atom, an aryl group such as an alkyl group, a cycloalkyl group or a phenyl group, preferably having 1 to 8 carbon atoms, or a heterocyclic group (e.g., a pyridyl group or a furyl group). R 9 represents a hydrogen atom, an alkyl group having preferably 1 to 8 carbon atoms, an aryl group such as a phenyl group, a cycloalkyl group, a heterocyclic group (such as a pyridyl group or a furyl group), or an amino group. Each group may have substitution.
    [115] Examples of such a substituent include an aryl group such as a halogen atom (fluorine atom and chlorine atom), a C1-C6 alkyl group and a phenyl group, a heterocyclic group (pyridyl group and furyl group), a nitro group, a cyano group, A C1-C4 alkylthio group, an arylthio group (such as a phenylthio group), a keto group, a sulfonamide group, a sulfamoyl group, a C1-C4 acylamino group, a carbamoyl group, a sulfonyl group, A sulfinyl group, a hydroxyl group, a carboxyl group, an amino group, and primary and secondary C1-C4 amino groups.
    [116] It is particularly preferable that the alkyl group represented by R 4 , R 5 and R 6 is a C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl or n-butyl group). These alkyl groups include those having substituent (s). Preferable examples of such substituents include a hydroxyl group, an alkoxyl group (e.g., methoxy group or ethoxy group), an alkylsulfonamide group (e.g., methanesulfonamide group), a sulfo group, a carboxyl group, a sulfamoyl group, and a carbamoyl group.
    [117] The anion represented by Z - is a known one, for example, I - , Br - , Cl - , ClO 4 - , CH 3 COO - , BF 3 -
    [118]
    [119] .
    [120] vii) Compound of Structural Formulas (8) to (11)
    [121] X e represents a chlorine ion, bromine ion, iodine ion, perchlorate ion, sulfonate ion, p- toluenesulfonate ion, methyl sulfate ion, ethyl sulfate ion, a propyl sulfate ion, borate ion tetrafluoroborate, tetraphenyl A sulfate ion, a sulfate ion, a borate ion, a hexafluorophosphate ion, a benzene sulfinate ion, an acetate ion, a trifluoroacetate ion, a propionate ion, a benzoate ion, an oxalate ion, a succinate ion, A sulfate ion, a citrate ion, a hydrogen phosphate ion, a dihydrogen phosphate ion, a pentachlorostannate ion, a chlorosulfonate ion, a fluorosulfonate ion, a trifluoromethanesulfonate ion, a hexafluoroantimonate ion, A molybdenate ion, a tungstate ion, a titanate ion, And anions such as zirconate ions and zirconate ions.
    [122] Examples of R 1 to R 7 include a hydrogen atom, a heavy hydrogen atom, a halogen atom (fluorine, chlorine, bromine and iodine atoms), an alkyl group (methyl, ethyl, (C1-C12 alkyl groups such as methyl, ethyl, propyl, butyl, t-butyl, n-amyl, t-amyl, n-hexyl, Such as 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxy Propyl, 2-chloroethyl, 3-chloropropyl, 2-fluoroethyl, 3-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2,2,2- , 3-sulfopropyl, 4-sulfobutyl, N- (methylsulfonyl) -carbamoyl, 2-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl, ≪ RTI ID = 0.0 > 3- ( Ethoxycarbonylethyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, 2-benzyl (2-methoxycarbonylethyl) C1-C6 alkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl groups; cyclic alkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl groups; C12 alicyclic groups such as allyl, isobutenyl and prenyl groups), alkenyl groups (such as vinyl, propenyl, isopropenyl, butenyl, pentenyl, hexenyl, (C1-C12 alkenyl group such as dodecanyl group), aralkyl group (C1-C12 aralkyl group such as benzyl, 2-phenylethyl, 3-phenylpropyl, KYLGY (including carboxybenzyl, sulfobenzyl, hydroxybenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, xylanyl, aminobenzyl, methoxycarbonylbenzyl (C1-C12 acyl groups such as acetyl, propionyl, butyroyl, valerolyl, benzoyl, tolyloyl, naphthoyl and phthaloyl groups), amino groups , Diethylamino, dipropylamino, dibutylamino, acetylamino, benzoylamino, diphenylamino, di-p-dimethylaminophenylamino and di-p-diethylaminophenylamino groups), thiol groups, Substituted thio groups such as methylthio, ethylthio, propylthio, butylthio, benzylthio, phenylthio, 2,4-dinitrophenylthio, p-methoxyphenylthio, p- And the like), a substituted or unsubstituted aryl group (phenyl, naphthyl, tolyl, xylyl, anthranyl, pyrenyl, fluorophenyl, chlorophenyl, ethylphenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, nitro Phenyl, aminophenyl, dimethylaminophenyl, diethylaminophenyl, dipropyl Phenylthiophenyl, dimethoxydiphenyl, trimethoxyphenyl and dimethoxydiphenyl groups), substituted or unsubstituted heteroaryl groups (e.g., substituted or unsubstituted heteroaryl groups, substituted or unsubstituted heteroaryl groups, The compound of formula (I) is preferably selected from the group consisting of benzoyl, benzyl, benzyl, benzyl, phenanthryl, Carbamoyl, carbazolyl and N-ethylcarbazolyl groups), substituted or unsubstituted styryl groups (styryl, methoxystyryl, dimethoxystyryl, trimethoxystyryl, ethoxystyryl, dimethylaminostyryl, Diethylaminostyryl, dipropylaminostyryl, dibenzylaminostyryl, diphenylaminostyryl, 2,2-diphenylvinyl, 2-phenyl-2-methylvinyl, 2- (dimethylaminophenyl) -2 (Vinylphenyl) -2-phenylvinyl, 2,2-di (diethylaminophenyl) vinyl, 2,2-di ( 2- (dimethylaminophenyl) -2-methylvinyl and 2- (diethylaminophenyl) -2-ethylvinyl groups, etc.), and substituted and non-substituted (Phenyl azo, -Naphthylazo, -Naphthylazo, dimethylaminophenylazo, chlorophenylazo, nitrophenylazo, methoxyphenylazo and tolylazo groups), and the like.
    [123] The compounds represented by the structural formula (1) can be synthesized, for example, by a synthesis method described in JP-A-63-95269. The compounds represented by the structural formula (2) can be synthesized, for example, by the synthetic method described in JP-A-3-316161. The compounds represented by the structural formulas (3) and (4) can be synthesized, for example, by the synthesis method described in JP-B-43-25335. The compounds represented by the structural formula (5) can be synthesized, for example, by the synthetic method described in JP-A-60-51166. The compounds represented by the structural formula (6) can be synthesized, for example, by the synthetic method described in JP-A-8-245895. The compounds represented by the structural formula (7) can be synthesized, for example, by the synthetic method described in JP-A-4-78579. Compounds represented by Structural Formulas (8), (9), (10) and (11) are disclosed, for example, in JP-A-62-123252, JP-A-3-226736, JP- -6-43583, European Patent 0430244A, and J. Am. Chem.Soc., 80, 3772-3777 (1958).
    [124] The compounds of formulas (1) to (11) may be provided in the form of their pharmacologically acceptable salts. These salts include, in addition to those mentioned above, those which are conventionally used as pharmacologically acceptable salts, for example, salts with acids such as hydrochloride, sulfate, phosphate, citrate and p-toluenesulfonate, and salts such as sodium salts and potassium salts Alkaline earth metal salts such as calcium salts and organic salts such as methylamine salts and ethylenediamine salts.
    [125] Some representative examples of these compounds useful as photochemical therapeutic agents of the present invention are given below. The wavelength (maximum absorption wavelength) at which these compounds exhibit maximum absorption is shown in Table 1.
    [126] Representative compounds
    [127] Polymethine type 1
    [128]
    [129] Polymethine type 2
    [130]
    [131] Polymethine type 3
    [132]
    [133] Polymethine type 4
    [134]
    [135] Naphthalocyanine type 5
    [136]
    [137] Anthracian type 6
    [138]
    [139] Complex Type 7
    [140]
    [141] Metal containing indian aniline type 8
    [142]
    [143] Diimonium type 9
    [144]
    [145] Aminium Type 10
    [146]
    [147] [Table 1]
    [148] The maximum absorption wavelength of representative compounds
    [149] Compound No. The maximum absorption wavelength ( Max) Polymethine type 1 Polymethine type 2 Polymethine type 3 Polymethine type 4 Naphthalocyanine type 5 Anthracenium type 6 Complex compound type 7 Metal containing indoline aniline type 8 Diimonium type 9 Aminium type 10 820 nm830 nm822 nm1045 nm840 nm800 nm nm860 nm840 nm1090 nm950 nm
    [150] As is apparent from Table 1, all of these compounds exhibit maximum absorption in the wavelength range of 800 to 1200 nm, thus enabling photochemotherapy treatment with high absorption efficiency.
    [151] The compounds used in the present invention, particularly the compounds of the structural formulas (1) to (11) or pharmacologically acceptable salts thereof have the following characteristics because they exhibit maximum absorption in the wavelength range of 800 to 1200 nm.
    [152] (A) Since the maximum absorption wavelength range is from 800 to 1200 nm, these compounds can be applied to a much deeper treatment of living tissue.
    [153] (B) These compounds are extremely active when exposed to light, so that they can, for example, dissolve such as solid tumors.
    [154] (C) Since these compounds have affinity for target cells such as cancer cells, infection sites can be treated extremely efficiently.
    [155] (D) Since these compounds hardly act on living organisms that are not exposed to light, their side effects are limited.
    [156] (E) Since these compounds are dissolved in a solvent, various dosage forms such as injections can be prepared by themselves.
    [157] The mechanism of action of the photochemotherapeutic agent of the present invention has not yet been fully elucidated. However, the therapeutic effect of the therapeutic agent is due to the exothermic effect of the compounds produced by their exothermic action and the generation of free radicals or similar molecular species in the molecule . Especially in the case of aminium type compounds, since they have free radicals in the molecule, their action by these free radicals is also considered.
    [158] The photochemical therapeutic agent of the present invention shows therapeutic effects on thrombosis, arteriosclerosis, myocardial system diseases and the like, but is useful as a therapeutic agent for tumors, especially cancer, and can also be used for the treatment of cancer that grows in deep parts of the body.
    [159] The photochemical therapeutic agent of the present invention is provided in the form of a commonly used pharmaceutical preparation such as an injection, a tablet, and a powder. A pharmaceutically acceptable carrier, lubricant, disintegrant, solvent, excipient, solubilizer, dispersant, stabilizer, suspending agent, preservative, analgesic agent, Can be used. In the case of injections, a solvent is usually used. As the solvent, a mixture of physiological saline, 5% glucose or mannitol, a water-soluble organic solvent [such as glycerol, ethanol, dimethyl sulfoxide, polyethylene glycol, Cremophor] . The amount of the compound exhibiting the maximum absorption in the wavelength range of 800 to 1200 nm in the formulation will vary depending on the kind of the compound to be used and the dosage form, but is usually 0.1 to 100% by weight. In the case of an injection, it is preferable that the compound exhibiting maximum absorption in a wavelength range of 800 to 1200 nm is contained at a concentration of 0.1 to 100 mg / ml. For example, water (physiological saline or the like) or a water-soluble organic solvent (ethanol, dimethyl sulfoxide, etc.) may be used as the solvent to be used. These solvents may be used singly or in a mixture of two or more.
    [160] The dosage of the photochemotherapeutic agent of the present invention varies depending on the patient's age, body weight, disease state, therapeutic effect, administration route, administration time and period (days), and other factors, Once every 4 weeks, every 3 to 6 times, 10 to 500 mg, preferably once every 4 weeks, all 5 times, in a dose of 100 to 500 mg.
    [161] The method for treating a tumor with a photochemical therapy according to the present invention is characterized in that the photochemotherapeutic agent is administered and then irradiated with a light beam in a wavelength range of 800 to 1200 nm. A tumor that can be treated is a solid tumor, which is divided into benign tumors and malignant tumors. Examples of benign tumors include papilloma, adenoma (polyp), lipoma, hemangioma, lymphangioma, fibroma, and black spots, and malignant tumors include carcinoma and sarcoma. Parenteral administration is recommended, but oral or parenteral administration is recommended. During injection, intravenous, intraarterial, subcutaneous injection, or direct injection into the infected area (tumor site). Preferably, the photochemotherapeutic agent is applied to the surface of the tumor by making it into liniment such as ointment, or injected directly into the tumor by injection.
    [162] The light used in the photochemical therapy of the present invention may be any wavelength as long as it has a wavelength band including the maximum absorption wavelength of the compound or a wavelength substantially equal to the maximum absorption wavelength of the compound contained in the therapeutic agent. A laser beam having a wavelength of 800 to 1200 nm, preferably a laser beam having such a wavelength, is usually used. The dose of light varies depending on the type and condition of the subject to be treated, the health condition of the patient, age, sex, body weight and sperm, the kind of compound used, and the like, but is usually in the range of 10 to 200 J / cm 2 . Only one type of light having a single wavelength or a single wavelength can be used, or two or more kinds of lights having different wavelengths or different wavelengths can be used.
    [163] The present invention will be described in detail with reference to the following Examples, but the scope of the present invention is not limited by these Examples.
    [164] Example 1 Acute Toxicity Test on Mice
    [165] 1) Method
    [166] The diimonium type compound 9 or the aminium type compound 10 is dissolved in dimethyl sulfoxide and the compound is dissolved in an appropriate solvent such that the compound can be administered at a dose of 150 mg / kg, 100 mg / kg, 25 mg / kg or 6.25 mg / The concentration of the solution was adjusted. Each solution was administered once intraperitoneally to CDF1 (female) mice in an amount of 0.05 ml per 20 g mouse body weight.
    [167] 2) Results
    [168] As a result of administering the diimonium type compound 9 or the aminium type compound 10, there was no mortality of the mice at the set dose of 150 mg / kg. In addition, there was no weight loss after administration and there was no indication of toxicity of each compound.
    [169] Example 2: Antitumor effect of human pharyngeal cancer HEp-2
    [170] 1) Method
    [171] Human pharyngeal cancer HEp-2 specimens were sliced into 2 mm 3 cubes and transplanted using a trocar under the skin at the back of BALB / c (female) nuold mice. When this tumor grew to a volume of about 200 mm 3 , it was used for treatment. A dimethylsulfoxide solution of diimonium type compound 9 or aminium type compound 10 was prepared by adjusting the concentration so that the dose of the compound was 150 mg / kg. 50 μl of this solution was administered to the tumor site of the anesthetized mouse, and the semiconductor laser light of wavelength 980 nm was irradiated to this site at a dose of 500 mW / cm 2 for 10 minutes to perform photodynamic therapy on the cancer . And the mice irradiated only with the laser light were compared with each other.
    [172] 2) Results
    [173] In the mice subjected to the photodynamic therapy using the diimonium type compound 9 or the aminium type compound 10, the tumor area became black on the day of laser irradiation and crust was formed. After 15 days of irradiation, the crust fell off and the tumor completely disappeared. On the other hand, in the mouse irradiated with the laser light alone, only a slight white spot was formed in the tumor site and the tumor continued to grow.
    [174] Example 3 Antitumor Effect on Human Pharyngeal Cancer HEp-2 Influenced by 1064 nm Laser Irradiation
    [175] 1) Method
    [176] Human pediatric HEp-2 specimens were transplanted into nuold mice in the same manner as in Example 2 and used in treatment studies when the tumor reached a volume of 100 mm 3 or greater. 50 μl of dimethylsulfoxide solution of diimonium type compound 9 or aminium type compound 10, whose concentration was adjusted so that the dose of the compound was 37.5 mg / kg or 150 mg / kg, was administered to the tumor site, Nd-YAG laser light was irradiated to the tumor site at a dose of 300 J / cm 2 , and photodynamic therapy was performed. And the mice irradiated only with the laser light were compared with each other.
    [177] 2) Results
    [178] In the mice subjected to the photodynamic therapy using the diimonium type compound 9 or the aminium type compound 10, the tumor area became black on the day of laser irradiation and crust was formed, and the tumor was finally necrotized . Surprisingly, when the diimonium type compound 9 was used, the tumor was completely phagocytosed and its growth was strongly inhibited. However, tumor necrosis did not occur in the case of a mouse as a control for irradiating only laser light and in the case of administration of a diimonium type compound 9 or an aminium type compound 10 and no irradiation of laser light. The results are shown in Table 2.
    [179] [Table 2] Tumor necrosis of the compounds of the present invention
    [180] The compound of the present inventionCompound dose (mg / kg)The dose (J / cm 2 )effect Control diimonium type compound 9 Aminium type compound 437.515030003000300Tumor growth Tumor growth Tumor necrosis Tumor growth Tumor Necrosis
    [181] Example 4: Hemostasis effect
    [182] 1) Method
    [183] Blood circulation in subcutaneous blood vessels of blood vessels or nude mice induced by tumor implanted in the same manner as in Example 2 was observed under a microscope. A diimonium type compound 9 or an aminium type compound 10 was administered subcutaneously or directly to a tumor. After a lapse of several minutes, 980 nm semiconductor laser light was irradiated to the compound administration site at an irradiation dose of 165 or 250 J / cm 2 . Images of blood circulation at the irradiated site were continuously monitored and recorded by a CCD camera.
    [184] 2) Results
    [185] The blood circulation in the blood vessels at the administration site of the diimonium type compound 9 or the aminium type compound 10 and its adjacent site was blocked by irradiation with laser light. The results are shown in Table 3.
    [186] [Table 3] Effects of the compounds of the present invention on blood circulation arresting effect
    [187] The compound of the present inventionConcentration (mg / ml)Administration siteThe dose (J / cm 2 )Hemostatic effect Control diemonium type compound 9 Aminium type compound 105505Subcutaneous tumors Subcutaneous subcutaneous250250250250250None Partial Partial Powerful Partial
    [188] week:
    [189] Strong: Almost all of the blood circulation at the compound administration site and its adjacent site is completely blocked.
    [190] Partial: Part of the blood circulation at the compound administration site and its adjacent site is completely blocked.
    [191] Weak: There is incomplete blockage of blood circulation at the compound administration site and its vicinity.
    [192] None: The blood circulation at the site of administration of the compound and its adjacent site is not blocked.
    [193] Therefore, it is suggested that the diimonium type compound 9 or the aminium type compound 10 reacts with the laser light to generate free radicals, and these free radicals have an injury effect on the endothelium of blood vessels and cause thrombosis.
    [194] A phototherapeutic therapeutic agent for tumors, particularly cancer, is realized using a therapeutic agent according to the present invention, which is a totally different kind from conventional porphyrinic drugs. In addition, the active ingredient of the therapeutic agent of the present invention exhibits maximum absorption in the long wavelength region of 800 to 1200 nm and has a strong absorption, thus making it possible to treat the tumor extremely efficiently. Moreover, these wavelength ranges are highly permeable to tissues, enabling the treatment of tumors, especially cancer, that grows deep within the body.
    权利要求:
    Claims (30)
    [1" claim-type="Currently amended] A photochemotherapeutic agent containing, as an active ingredient, a compound exhibiting maximum absorption in a wavelength range of 800 to 1200 nm.
    [2" claim-type="Currently amended] A photochemotherapeutic agent containing a diimonium compound as an effective ingredient exhibiting maximum absorption in a wavelength range of 800 to 1200 nm.
    [3" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 2, wherein the diimonium compound is a compound having a skeleton structure represented by the following structural formula (12).

    [4" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 2, wherein the diimonium compound is a compound represented by the following structural formula (3) or a pharmacologically acceptable salt thereof.

    Wherein R 1 to R 8 independently represent a C1 to C12 substituent, X represents an anion, n is a number of 1 or 2, the ring A and the four rings B independently of one another are each substituted with 1 to 4 substituents .
    [5" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 4, wherein each of R 1 to R 8 is a hydrophobic group.
    [6" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 4, wherein R 1 to R 8 are each a C 1 to C 5 alkyl group, and ring A and four rings B have no substituent.
    [7" claim-type="Currently amended] A photochemotherapeutic agent containing an aminium compound exhibiting maximum absorption in a wavelength range of 800 to 1200 nm as an active ingredient.
    [8" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 7, wherein the aminium compound is a compound having a skeleton structure represented by the following structural formula (13).

    In the above formula, m is a number of 1 or 2.
    [9" claim-type="Currently amended] 8. The photochemotherapeutic agent according to claim 7, wherein the aminium compound is a compound represented by the following structural formula (4) or a pharmacologically acceptable salt thereof.

    Wherein R 1 to R 8 independently represent a C1 to C12 substituent, X represents an anion, n is a number of 1 or 1/2, m is a number of 1 or 2, and one or two rings A and / The four rings B may independently have 1 to 4 substituents each independently of each other.
    [10" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 9, wherein each of R 1 to R 8 is a hydrophobic group.
    [11" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 9, wherein R 1 to R 8 are each a C 1 to C 5 alkyl group, m is 1, and ring A and four rings B have no substituent.
    [12" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 1, wherein the compound is a naphthalocyanine compound or an anthracene compound.
    [13" claim-type="Currently amended] 13. The photochemotherapeutic agent according to claim 12, wherein the compound is a compound represented by the following structural formula (1) or (2) or a pharmacologically acceptable salt thereof.


    Wherein X represents an oxygen atom, a sulfur atom, NH, SO 2 , CO or a single bond; R 1 represents an optionally substituted aryl, aralkyl or alkyl group, an alkoxyl group, an alkylamino group or a hydroxyl group; k, l, m and n each represent an integer of 0 to 4; when k + 1 + m + n is 2 or more, R 1 and X may be the same or different; M represents at least one of a ligand such as a halogen atom, a hydroxyl group, an aryloxy group, an alkoxyl group, a trialkylsiloxy group, a triarylsiloxy group, a trialkoxysiloxy group, a triaryloxysiloxy group, Or a metal oxide or a metal which may be present in the atmosphere.
    [14" claim-type="Currently amended] The phototherapeutic agent according to claim 1, wherein the compound is a complex or a pharmacologically acceptable salt thereof represented by the following structural formula (5).

    Wherein R 1 to R 4 independently represent a hydrogen atom or an optionally substituted alkyl, aryl, alkylthio or arylthio group, or R 1 and R 2 and / or R 3 and R 4 bond to each other to form a substituent And M represents Ni, Pd, Co, VO, Cu or Pt.
    [15" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 1, wherein the compound is a bissquarilium compound.
    [16" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 15, wherein the compound is a compound represented by the following structural formula (6) or a pharmacologically acceptable salt thereof.

    In the above formula, Ring A and Ring B independently represent a heterocycle having a nitrogen atom, and X represents a benzene ring substituted by a group of the following structural formula or an alkylamino group.

    (In the above formula, ring C represents a heterocycle having a nitrogen atom.)
    [17" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 1, wherein the compound is a metal-containing indoaniline compound.
    [18" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 17, wherein the compound is a compound represented by the following structural formula (7) or a pharmacologically acceptable salt thereof.

    In the above formula, M represents a chelated metal ion; R 1 represents a hydrogen atom, an optionally substituted alkyl, aryl, arylalkyl, alkoxyl, alkylamino or alkylaminocarbonyl group, a halogen atom, a hydroxyl group, an amino group, an acylamino group, a sulfonylamino group, an aminocarbonyl group or a nitro group; R 2 and R 3 independently represent a halogen atom or a monovalent organic group; X is a group represented by the following structural formula,

    -OR 6 or a hydroxyl group; Z - represents an anion; R 4 , R 5 and R 6 independently represent an optionally substituted alkyl group; m and n are each an integer of 0 to 3, and when m and n are each 2 or more, R 2 and R 3 may be the same or different.
    [19" claim-type="Currently amended] The method according to claim 1, wherein the compound is selected from the group consisting of polymethine or other types of compounds represented by any one of structural formulas (8) to (11) below (excluding indocyanine type compounds) or pharmacologically acceptable Photochemotherapy therapies.



    R 1 to R 7 independently represent a monovalent organic group such as a hydrogen atom, a halogen atom, an optionally substituted alkyl group, a hydroxyl group, an optionally substituted alkoxyl group or an amino group, a saturated alicyclic group, an unsaturated alicyclic group, R 1 to R 3 , R 2 to R 4 , R 3 to R 5 , R 4 to R 6 and R 5 to R 7 each independently represent a hydrogen atom, a halogen atom, a halogen atom, At least one of the combinations may form one ring which may be a 5-membered, 6-membered or 7-membered substituted or unsubstituted saturated alicyclic ring, an unsaturated alicyclic ring, a saturated heterocyclic ring, an aromatic ring, A condensed ring or a good ring; A to D independently represent a hydrogen atom, an optionally substituted aromatic ring, a heteroaromatic ring, a substituent represented by any one of the following structural formulas

    (Wherein the substituted or unsubstituted condensed ring is ROne~ R2, R2~ R3, R3~ R4, R5~ R6And R6~ R7, Or a group having a heteroatom in the azulene skeleton, provided that at least two of A to D are not hydrogen atoms at the same time; ROne~ R7Is selected from the above monovalent organic moieties, R14 And R15Is selected from the above-mentioned monovalent organic residue or an optionally substituted phenyl group; A-B and C-D may form a ring to form a group represented by any one of the following formulas

    [Wherein R 8 and R 9 independently represent an aromatic ring, a styryl group or a heteroaromatic ring group which may be substituted with a monovalent organic residue such as a halogen atom, an alkyl group, a hydroxyl group, an alkoxyl group and an amino group; And X represents a hetero atom such as an oxygen atom, a sulfur atom, a selenium atom and a tellurium atom, or a substituted nitrogen atom or a group represented by the following structural formula.

    (Wherein Y represents a hetero atom such as an oxygen atom, a sulfur atom, a selenium atom and a tellurium atom, a substituted or unsubstituted methylene group, or a substituted nitrogen atom, but R 1 to R 7 are the same or different, Selected)];
    X represents an anion.
    [20" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 1, wherein the compound has a radical in the molecule.
    [21" claim-type="Currently amended] 21. The phototherapeutic agent according to any one of claims 1 to 20, which contains a pharmacologically acceptable carrier.
    [22" claim-type="Currently amended] 22. The therapeutic agent for photochemotherapy according to claim 21, wherein the pharmacologically acceptable carrier is a solvent.
    [23" claim-type="Currently amended] 23. The therapeutic agent for photochemotherapy according to claim 22, which contains the compound according to any one of claims 1 to 20 in a concentration of 0.1 to 100 mg / ml.
    [24" claim-type="Currently amended] 24. The phototherapeutic agent according to claim 22 or 23, wherein the solvent is physiological saline, a 5% glucose solution or a mannitol solution.
    [25" claim-type="Currently amended] The therapeutic agent for photochemotherapy according to claim 22 or 23, wherein the solvent is a water-soluble organic solvent such as glycerol, ethanol, dimethylsulfoxide, polyethylene glycol or Cremophor.
    [26" claim-type="Currently amended] 24. The phototherapeutic agent according to claim 22 or 23, wherein the solvent is a mixture of water and a water-soluble organic solvent.
    [27" claim-type="Currently amended] 27. The therapeutic agent for photochemotherapy according to claim 25 or 26, wherein the water-soluble organic solvent is dimethylsulfoxide or ethanol.
    [28" claim-type="Currently amended] 27. A method of treating photochemotherapy of a tumor, comprising administering a therapeutic agent for photochemotherapy according to any one of claims 1 to 27 followed by irradiation with a beam of light in the wavelength range 800 to 1200 nm.
    [29" claim-type="Currently amended] 29. The method according to claim 28, wherein the administration is carried out by applying a therapeutic agent for photochemotherapy to the tumor surface or directly injecting a therapeutic agent for photochemotherapy into the tumor.
    [30" claim-type="Currently amended] 29. The photochemical therapy method according to claim 28, wherein the light beam is a laser beam.
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    同族专利:
    公开号 | 公开日
    EP1120119A4|2003-10-01|
    CN1323224A|2001-11-21|
    US6500816B1|2002-12-31|
    WO2000016806A1|2000-03-30|
    CA2342602A1|2000-03-30|
    AU5651799A|2000-04-10|
    EP1120119A1|2001-08-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-09-17|Priority to JP26324998
    1998-09-17|Priority to JP1998-263249
    1999-09-16|Application filed by 다께다 가즈히꼬, 니폰 가야꾸 가부시끼가이샤
    1999-09-16|Priority to PCT/JP1999/005038
    2001-08-09|Publication of KR20010075107A
    优先权:
    申请号 | 申请日 | 专利标题
    JP26324998|1998-09-17|
    JP1998-263249|1998-09-17|
    PCT/JP1999/005038|WO2000016806A1|1998-09-17|1999-09-16|Remedies for photochemotherapy|
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