Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-12
2002-12-31
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C424S009610, C424S009362, C430S270100
Reexamination Certificate
active
06500816
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a photochemotherapeutic agent which is effective for the treatment of, for example, tumors, especially carcinomas.
BACKGROUND ART
Presently, photochemotherapy is in practice as one of the effective therapeutics for tumors such as carcinomas. Studies on photochemotherapy were begun relatively early, and its clinical application was practiced in as early as 1976. A lot of literatures and patents on this subject have been issued, an example of which is a review by Michael J. Manya et al (J. Clin. Oncology, 6, 380, 1988). According to these literatures and patents, the compounds which have hitherto been studied and clinically applied as photochemotherapeutic agents are mostly the porphyrin-based compounds, and in Japan at present, Nippon Lederle is marketing dihematoporphyrin under the trade name of Photofrin®.
The photochemotherapy using such porphyrin-based compoudns are explained below.
When a drug is administered to a cancer patient (in case no surgical treatment is involved, the type of cancer to which the said therapeutics can be applied is limited in principle to cancer at the region close to the body surface, such as skin cancer, etc.), the best part of the drug is metabolized in the normal cells in several days, whereas the drug taken up by the cancerous cells stays left in the cells. The amount of the drug left in the cancerous cells is several to several ten times that in the normal cells. When light with a wavelength of 600 to 700 nm is applied to the cancerous cells, only these cells holding the drug die out specifically while the normal cells remain unaffected. The reason why the drug stays left in the cancerous cells alone is yet to be elucidated, but it is considered that this phenomenon is due to the difference in blood flowing condition between the normal and cancerous cells, or the difference in activity of the immune system such as lymphoid cells, etc. Also, no definite explanation is available on the reason why the cancerous cells holding the drug are killed by the application of light, but this seems to be attributable to the transformation of ambient oxygen into singlet oxygen having stronger toxicity by the transfer of energy from the drug activated by light exposure.
However, photochemotherapy using the said porphyrin-based compounds has some problems. One of such problems is in the relation between the absorption wavelength of the compound itself and the wavelength of light used for the treatment. The wavelength of light used for the treatment is preferably not less than 600 nm as it is required that the light applied won't be scattered or absorbed by the matters in the living body, and that no influence be given to the hemoglobin of the erythrocytes, and so on. However, absorption of light by, for instance, Photofrin® mentioned above as a commercial product of dihematoporphyrin in the wavelength region of not less than 600 nm is only 2 to 3% of that at the maximum absorption wavelength, 363 nm, of this compound. There is therefore no alternative but to practice a photochemotherapy which is actually very bad in efficiency, and this produces the necessity of increasing dosage of the drug or exposure dose of light, resulting in an increase of side effects or a rise of equipment cost.
Another problem is phototoxicity of the porphyrin-based compounds in the skin, etc., and because of this, the drug-administered patient is obliged to lead a life avoiding exposure to light such as sunlight for about 6 to 8 weeks. Still another problem is the limited range of treatment since the penetration into the tissue of the light rays of a wavelength region of around 630 nm is only several mm. This has been an obstacle to the clinical application of the above compounds.
DISCLOSURE OF THE INVENTION
The present invention is intended to provide an utterly new type of photochemotherapeutic agent for solving the said prior art problems.
The present inventors found out a photochemotherapeutic agent having high tissue penetrability and strong absorbability from among the functional pigments, and attained the present invention on the basis of this finding. Thus, the present invention relates to the following items of disclosure (1) to (30).
(1) A photochemotherapeutic agent comprising as an active ingredient a compound showing maximum absorption at wavelengths from 800 to 1,200 nm.
(2) A photochemotherapeutic agent comprising as an active ingredient a diimonium type compound showing maximum absorption in the wavelength region of 800 to 1,200 nm.
(3) A photochemotherapeutic agent according to (2) above, wherein the diimonium type compound is a compound having a skeletal structure represented by the formula (12):
(4) A photochemotherapeutic agent according to (2) above, wherein the diimonium type compound is a compound represented by the following formula (3) or its pharmacologically acceptable salt:
wherein R
1
to R
8
represent independently a C1-C12 substituent; X represents an anion: n is a number of 1 or 2; and ring A and four ring B's may have independently of each other 1 to 4 substituents.
(5) A photochemotherapeutic agent according to (4) above, wherein R
1
to R
8
are each a hydrophobic group.
(6) A photochemotherapeutic agent according to (4) above, wherein R
1
to R
8
are each a C1-C5 group, and ring A and four ring B's have no substituent.
(7) A photochemotherapeutic agent comprising as an active ingredient an aminium type compound showing maximum absorption in the wavelength region of 800 to 1,200 nm.
(8) A photochemotherapeutic agent according to (7) above, wherein the aminium type compound is a compound having a skeletal structure represented by the formula (13):
wherein m is a number of 1 or 2.
(9) A photochemotherapeutic agent according to (7) above, wherein the aminium type compound is a compound represented by the following formula (4) or its pharmacologically acceptable salt:
wherein R
1
to R
8
represent independently a C1-C12 substituent; X represents an anion; n is a number of 1 or 1/2; m is a number of 1 or 2; and 1 or 2 ring A's and four ring B's may have independently of each other 1 to 4 substituents.
(10) A photochemotherapeutic agent according to (9) above, wherein R
1
to R
8
are each a hydrophobic group.
(11) A photochemotherapeutic agent according to (9) above, wherein R
1
to R
8
are each a C1-C5 alkyl group, m is 1, and ring A and four ring B's have no substituent.
(12) A photochemotherapeutic agent according to (1) above, wherein the compound is a naphthalocyanine type compound or an anthracyanine type compound.
(13) A photochemotherapeutic agent according to (12) above, wherein the compound is a compound of the following formula (1) or (2) or its pharmacologically acceptable salt:
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 represent respectively an integer of 0 to 4, and when k+l+m+n is equal to 2 or greater, R
1
and X may be identical or different; and M represents a metal or an oxidized metal which may have coordinated therein one or more of the ligands 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, a trityloxy group, an acyloxy group, etc.
(14) A photochemotherapeutic agent according to (1) above, wherein the compound is a complex compound represented by the following formula (5) or its pharmacologically acceptable salt:
wherein R
1
to R
4
represent independently 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
may combine with each other to form a ring having a substituent; and M represents Ni, Pd, Co, VO, Cu or Pt.
(15) A photochemotherapeutic agent according to (1) above, wherein the compound is a bissquarilium type compound.
(16) A photochemotherap
Ekimoto Hisao
Onishi Masao
Sakai Teruyuki
Seno Chieko
Kwon Brian
Nields & Lemack
Nippon Kayaku Kabushiki Kaisha
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