WO2007023766A1 - Singlet oxygen generators having silicon-containing substituents - Google Patents

Abstract

Compounds represented by the general formulae (I) to (III) are used as the active ingredient of singlet oxygen generators: (I) (II) (III) wherein at least one of R1 to R14 in the general formula (I) is a substituent selected from among groups (i) to (iv); at least one of R1 to R16 in the general formula (II) is a substituent selected from among groups (i) to (iv); and at least one of R1 to R12 in the general formula (III) is a substituent selected from among groups (i) to (iv): (i) (ii) (iii) (iv) (wherein Ra, Rb and Rc are each independently hydrogen or a substituent selected from among methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, phenyl, methoxy, ethoxy and trimethylsilyl.

Description

 Specification

 Singlet oxygen generator introduced with a carbon-containing substituent

 Technical field

 [0001] The present invention relates to a singlet oxygen generator into which a carbon-containing substituent is introduced. The present invention also relates to a cancer therapeutic agent containing the singlet oxygen generator.

 Background art

 [0002] A compound capable of generating singlet oxygen (sensitizing dye) is administered to a patient such as cancer and irradiated with light of an appropriate wavelength to generate singlet oxygen, thereby destroying malignant cells and causing disease. There is a known method of phototherapy (photodynamic therapy). In such treatment methods, porphyrin analogs 'phthalocyanine derivatives' hypocrellin derivatives'hypericin derivatives and the like have been conventionally used (see, for example, Patent Documents 1 and 2 and Non-Patent Document 1). However, there have been few known examples using compounds having a substituent containing a cage.

 Patent Document 1: JP 2002-523509 A

 Patent Document 2: JP 2004-002438 A

 Non-Patent Document 1: Coordination Chemistry Reviews, 248 (2004), p321-350

 Disclosure of the invention

 [0003] An object of the present invention is to provide a singlet oxygen generator that can efficiently generate singlet oxygen and is suitably used for the treatment of cancer and the like.

 [0004] The present inventor has intensively studied to solve the above problems. As a result, it was found that the efficiency of singlet oxygen generation is increased by introducing a substituent containing silicon into compounds such as porphyrin analogues and phthalocyanine derivatives. Furthermore, it has been found that a singlet oxygen generator useful for the treatment of cancer or the like can be obtained by using a compound having such a carbon-containing substituent introduced therein, and the present invention has been completed.

That is, the present invention is as follows.

A singlet oxygen generator containing one or more compounds selected from the group of compounds represented by the following formulas (I) to (ΠΙ): [Chemical 1]

一般式 (I)において、 R〜R の少なくとも 1つは下記 (i)〜（iv)より選ばれる置換基で

In general formula (I), at least one of R to R is a substituent selected from the following (i) to (iv):

 1 14

In general formula (II), at least one of R to R is a group selected from the following (i) to (iv):

 1 16

In general formula (III), at least one of R to R is selected from the following (i;) to (iv)

 1 12

It is a substituent.

一般式（i)〜（iv)において、 Ra、 Rb、 Rcは独立して水素、メチノレ、ェチル、 n—プロピ ル、イソプロピル、 n—ブチル、イソブチル、 t—ブチル、フエニル、メトキシ、エトキシ、 トリメチルシリルより選ばれる置換基である。 [Chemical 2]

In the general formulas (i) to (iv), Ra, Rb and Rc are independently hydrogen, methylol, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, phenyl, methoxy, ethoxy and trimethylsilyl. It is a substituent selected from more.

 In general formula (I), R to R other than the substituents selected from the above (i) to (iv) are small.

1 14 each is a substituent having so ³ — or COO—, and at least one of R to R other than the substituent selected from the above (i) to (iv) in the general formula (Π) Has power 0 ³ —or COO—

 1 16

R to R other than the substituent selected from the above (i) to (iv) in the general formula (ΙΠ)

It is preferable that the substituent has at least one of 1 1 ο ³ —or coo—.

2

Of the compounds (ii) to (ii), compounds represented by the following formula (IV), (V), (VI) or (VII), which are preferred for the compound (ii), are particularly preferred.

本発明はまた、上記の一重項酸素発生剤を含むがん治療薬を提供する。

The present invention also provides a cancer therapeutic agent comprising the above singlet oxygen generator.

 The present invention also provides a method of administering the above compound to a patient and irradiating the compound with light to generate singlet oxygen.

 The present invention also provides the use of the above compound as a singlet oxygen generator.

The present invention also provides compounds represented by the following formulas (VIII) to (X).

一般式 (Vin)〜（X)において、 Ra、 Rb、 Rcは独立して水素、メチノレ、ェチル、 n—プロ ピル、イソプロピノレ、 n—ブチル、イソブチル、 t—ブチル、フエニル、メトキシ、エトキシ 、トリメチルシリルより選ばれる置換基である。

In the general formulas (Vin) to (X), Ra, Rb, and Rc are independently hydrogen, methylol, ethyl, n-propyl, isopropylinole, n-butyl, isobutyl, t-butyl, phenyl, methoxy, ethoxy, It is a substituent selected from trimethylsilyl.

 These compounds are synthesized according to the following SiSiTPP, Si TPP, and SiTPPS synthesis methods.

 2

 Ability to do S.

 Brief Description of Drawings

 [0007] FIG. 1 shows a singlet oxygen spectrum by SiTPP and a singlet oxygen spectrum by 5,10,15,20-tetraphenylporphyrin (TPP).

 FIG. 2 shows the spectrum of singlet oxygen by SiTPP and the spectrum of singlet oxygen by perinaphthenone (PN).

 BEST MODE FOR CARRYING OUT THE INVENTION

[0008] The present invention is described in detail below.

 In the present invention, the “singlet oxygen generator” refers to a substance that can generate singlet oxygen when irradiated with light.

The singlet oxygen generator of the present invention includes one or more compounds selected from the group of compounds represented by the following formulas (I) to (III). [Chemical 5]

一般式 (I)において、 R〜R の少なくとも 1つは下記 (i)〜（iv)より独立して選ばれる

In general formula (I), at least one of R to R is independently selected from the following (i) to (iv)

 1 14

In general formula (II), at least one of R to R is independently selected from the following (i) to (iv):

 1 16

And in the general formula (III), at least one of R to R is as follows:

 1 12

 0) to (iv) are independently selected substituents.

Among (i) to (i _v ), (m) or (iv) is preferable, and (m) is particularly preferable. In the formula (in), it is particularly preferable that one -SiRaRbRc is introduced at the 4-position, or two at the 3- and 5-positions.

一般式（i)〜（iv)において、 Ra、 Rb、 Rcは独立して水素、メチノレ、ェチル、 n—プロ ピル、イソプロピノレ、 n—ブチル、イソブチル、 tーブチル、フエニル、メトキシ、エトキシ 、トリメチルシリルより選ばれる置換基である。 [Chemical 6]

In the general formulas (i) to (iv), Ra, Rb, and Rc are independently hydrogen, methylol, ethyl, n-propyl, isopropylinole, n-butyl, isobutyl, t-butyl, phenyl, methoxy, ethoxy, trimethylsilyl. It is a substituent selected from more.

 In the compounds of the general formulas (I) to (III), n (n is an integer from 1 to 16)

At least one of them is a substituent selected from (i) to (iv).

Not limited. Other Rs are preferably the following substituents.

 n

1 H, -COOH (-COO-), -CH COOH (-CH COO "), -CH CH COOH (-CH CH CO

 2 2 2 2 2 2

○-), 10H, -SO H (-SO "), -CH, -CH CH, -CH (CH), -CH COCH CH (CH CO

 3 3 3 2 3 3 2 2 2 2

○ H) COOH (—CH COCH CH (CH COO—) COO—)

 2 2 2

Introducing so ³ — or COO— can give water solubility to the compound. Therefore, other R's contain at least one substituent with SO ³ — or COO— n

 That power S favored.

Ca²⁺などのイオンが配位していてもよいし、水 素原子が結合していてもよい。 SO ³ — and COO— are Na ⁺ ,

An ion such as Ca ²⁺ may be coordinated or a hydrogen atom may be bonded.

A compound having a substituent containing SO ³ — or COO— as R is a substituent n containing SO ³ — or COO—.

 In a known porphyrin analog having a hydrogen atom, it is possible to obtain a force S by introducing a carbon-containing substituent.

 [0010] The compound represented by the general formula (I) can be synthesized, for example, as follows.

[Chemical 7]

 [0011] The compound represented by the general formula (II) can be synthesized, for example, as follows.

[Chemical 8]

[0012] The compound represented by the general formula (m) can be synthesized, for example, as follows.

なお、一般式（m)で表される化合物においては、 R、 R、 R、 R が上記（m)または [Chemical 9]

In the compound represented by the general formula (m), R, R, R, and R are the above (m) or

 3 6 9 12

 It is preferable that the substituent is (iv). R, R, R, and R are the substituents of (iii) above.

 3 6 9 12

 More preferred.

 [0013] As the singlet oxygen generator of the present invention, 5, 10, 15, 20-tetrakis (4-trimethylsilylphenyl) porphyrin (SiTPP) represented by the following formula (IV), or An example is 5,10,15,20-tetrakis (4-pentamethyldisilylphenyl) porphyrin (SiSiTPP) represented by (V).

 [Chemical 10]

[0014] These compounds can be synthesized, for example, as follows.

[Chemical 11]

" e,SiMe, ₂ l)j n_D-_MBu_FLi

"e, SiMe, ₂ l) jn _D - _M Bu _F Li

 Ether

本発明の一重項酸素発生剤として別の特に好ましい形態としては、下記式 (VI)で 表される 5，10，15，20 -テトラキス (3, 5-ビストリメチジシリルフエニル)ポルフィリン（Si TPP)

Another particularly preferred form of the singlet oxygen generator of the present invention is 5,10,15,20-tetrakis (3,5-bistrimethydisilylphenyl) porphyrin (Si) represented by the following formula (VI): TPP)

 2

Or 5, 10, 15,20-tetrakis (3-trimethyldisilyl — 5-sulfophenyl) porphyrin (SiTPPS) represented by the following formula (VII).

[Chemical 12]

これらの化合物は、例えば、以下のようにして合成することができる。

These compounds can be synthesized, for example, as follows.

[Chemical 13]

^B

本発明の一重項酸素発生剤は、医薬製剤の製造法で一般的に用いられている公 知の手段に従って、上記一般式 (I)〜（III)から選択される化合物をそのままあるいは 薬理学的に許容される担体と混合して、例えば、錠剤、液剤、注射剤等の医薬製剤 として、経口的または非経口的（例、局所、静脈投与等）に投与することができる。な お、一般式 α)〜（πι)の化合物はがん組織に蓄積しやすいため、単独で投与しても よいが、リボソームなどを用いた薬品輸送システム (DDS)の手法により、標的組織に到 達しやすレ、ような形で投与してもよレ、。

The singlet oxygen generator of the present invention is a compound selected from the above general formulas (I) to (III) as it is or pharmacologically according to known means generally used in the production of pharmaceutical preparations. For example, a pharmaceutical preparation such as a tablet, solution, injection, etc. Can be administered orally or parenterally (eg, topical, intravenous administration, etc.). The compounds of the general formulas α) to (πι) are easy to accumulate in cancer tissue and may be administered alone, but they can be administered to the target tissue by a drug delivery system (DDS) method using ribosomes. It is easy to reach, and it can be administered in such a form.

In addition, the compounds of general formulas (Ι) to (こ と) may be those in which a metal such as Zn ²⁺ , Cu ⁺ (II), Ca ²⁺ , Mg ²⁺ or SiR is bonded to the center of the ring. .

 2

 [0018] The content of the compounds of the general formulas (i) to (ii) in the preparation is about 0.01 to about 100% by weight of the whole preparation. The dosage of the compounds of the general formulas (Ι) to (III) varies depending on the administration subject, target organ, symptom, administration method, etc., and is not particularly limited, but is generally about 0.1 to about 1 to: 1000 mg, preferably about 1.0 to:! OOmg.

 [0019] Examples of pharmacologically acceptable carriers include excipients, lubricants, binders and disintegrants in solid preparations, or solvents, solubilizers, suspending agents, and isotonicity in liquid preparations. Agents, buffering agents, soothing agents and the like. If necessary, additives such as conventional preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents can be used in appropriate amounts.

—In order to generate triplet oxygen and use it for photodynamic therapy, the compound of the general formulas (I) to (III) is administered and then irradiated with light of an appropriate wavelength.

 The irradiation time is appropriately selected depending on the age and sex of the patient, the type and degree of the disease, the distance between the light source and the affected part, and the like. The wavelength is not particularly limited as long as it can generate singlet oxygen, but 600 to 800 nm is preferable when performing photodynamic therapy. Irradiation may be performed from outside the body, and an optical fiber or the like may be inserted in the vicinity of the target tissue. In addition, an embodiment is also included in which bone marrow is removed from a leukemia patient, treated with the compounds of general formulas (I) to (i) in vitro, and the treated bone marrow is returned to the patient.

[0021] Cells can be destroyed by generating singlet oxygen. Therefore, the disease to which the singlet oxygen generator of the present invention can be applied is not particularly limited as long as it can be treated by generating singlet oxygen and destroying the cells. Examples include host-to-host diseases, transplant rejection, autoimmune diseases and T cell-mediated immune allergies, bacterial infections, viral infections, age-related macular degeneration, and acne. In this Then, cancer is particularly preferable. The type of cancer is not particularly limited. , Rectal cancer, etc.), breast cancer, ovarian cancer, disseminated multiple myeloma, bladder cancer, leukemia (eg, acute leukemia including acute transformation of chronic myelogenous leukemia), kidney cancer, prostate cancer, etc. .

 Example

 [0022] The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to the following examples.

[0023] Synthesis of 5, 10, 15,20-tetrakis (4-trimethylsilylphenyl) porphyrin>

 According to the method described in Bao-Hui Ye and Yosinori Naruta, Tetrahedron 59 (2003) 3593-3601, 5, 10, 15, 20_tetrakis (4_trimethylsilylphenyl) porphyrin ½01 ^) was synthesized.

 Specifically, it was synthesized by the following procedure.

 1,4-Dibromobenzene was lithiated with an equivalent amount of n-butyllithium in jetyl ether at _78 ° C and then reacted with chlorotrimethylsilane to give 88% yield of p_bromotrimethylsilanol. Benzene was obtained. This was lithiated with an equal amount of n-butyllithium in jetyl ether, dried at room temperature, and reacted in the presence of Ν, Ν, -dimethylformamide to give 75% Ρ-trimethylsilylbenzaldehyde. The yield was obtained.

 This was dissolved in black mouth form, an equal amount of pyrrole was added, and nitrogen was blown for 10 minutes. BF (OEt was added to this and allowed to react at room temperature. After that, it was reacted with 2,3_dichloro_5,6_disiano-1,4_benzoquinone. 15, 20-Tetrakis (4-trimethylsilylphenyl) porphyrin (SiTPP) (Formula IV) was obtained.

く 5, 10, 15,20-テトラキス (4-ペンタメチルジシリルフエニル)ポルフィリンの合成 > [Chemical 15]

Synthesis of 5, 10, 15,20-tetrakis (4-pentamethyldisilylphenyl) porphyrin>

 5, 10, 15, 20-Tetrakis (4-pentamethyldisilylphenyl) porphyrin (SiSiTPP) was synthesized by the following procedure.

 1,4-Dibromobenzene was lithiated with an equivalent amount of n-butyllithium in jetyl ether at -78 ° C and then reacted with black-opened pentamethyldisilane to obtain p-bromotrimethylsilylbenzene. It was.

This was lithiated with an equal amount of n-butyllithium in jetyl ether, and then dried at room temperature, and reacted in the presence of Ν, Ν, -dimethylformamide to obtain Ρ-pentamethyldisiline benzaldehyde. .

 This was dissolved in black mouth form, an equal amount of pyrrole was added, and nitrogen was blown for 10 minutes. BF (OEt was added to this and reacted at room temperature. After that, it was reacted with 2,3_dichloro_5,6_disiano-1,4_benzoquinone, and 5, 10, 15, 20-tetrakis ( 4-Pentamethyldisilylphenyl) porphyrin (SiSiTPP) (formula V) was obtained.

く 5, 10, 15,20-テトラキス (3, 5-ビストリメチジシリルフエニル)ポルフィリンの合成〉[Chemical 16]

Synthesis of 5, 10, 15, 20-tetrakis (3, 5-bistrimethyldisilylphenyl) porphyrin>

5, 10, 15, 20-Tetrakis (3, 5-bistrimethydisilylphenyl) porphyrin (Si2TPP) was synthesized by the following procedure.

 1,3,5-Tribromobenzene was lithiated with an equivalent amount of n-butyllithium in jetyl ether at -78 ° C and then reacted with black-opened pentamethyldisilane to give 1-bromo_3,5_bis Trimethylsilylbenzene was obtained.

This was lithiated with an equivalent amount of n-butyllithium in jetyl ether, and then dried at room temperature and reacted in the presence of Ν, Ν, -dimethylformamide to give 3,5-bistrimethylsilino benzaldehyde. It was.

 This was dissolved in black mouth form, an equal amount of pyrrole was added, and nitrogen was blown for 10 minutes. BF (OEt was added to this and reacted at room temperature. After that, it was reacted with 2,3_dichloro_5,6_disiano-1,4_benzoquinone, and 5, 10, 15, 20-tetrakis ( 3,5-bistrimethyldisilylphenyl) porphyrin (Si2TPPS) (formula VI) was obtained.

[Chemical 17]

<Synthesis of 5, 10, 15,20-tetrakis (3-trimethydisilyl-5-sulfophenyl) porphyrin> 5, 10, 15, 20-tetrakis (3_trimethyldisilyl-5-sulfophenyl) porphyrin Ding? ? 3) was synthesized by the following procedure.

 5, 10, 15, 20-tetrakis (3, 5-bistrimethydisilylphenyl) porphyrin (Si2TPPS) (formula VI) was reacted with CISO SiMe in carbon tetrachloride, followed by the addition of IN NaOH aqueous solution 5, 1

 3 3

 0,15,20-tetrakis (3-trimethyldisilyl-5-sulfophenyl) porphyrin (SiTPPS) (formula VII) was obtained.

[Chemical 18]

 As comparative compounds, the following 5,10,15,20-tetraphenylporphyrin (TPP) and perinaphthenone (ΡΝ) were used.

[Chemical 19]

[0028] <Generation of singlet oxygen>

 Each compound of TPP and SiTPP was dissolved in ethanol at an absorbance of 0.1, and then irradiated with 355 nm light using YAG LASER (Lotis Til LS-2137U). For the measurement of singlet oxygen, a self-made infrared emission measuring device using a photomultiplier tube for near infrared (Hamamatsu Photonitas R5509-42) was used. The measurement was performed 17 times, and the average value is shown in Fig. 1. The results are shown in Fig. 1. The phosphorescence spectrum of singlet oxygen sensitized by the compound was measured at max = 1270 nm. The amount of singlet oxygen by SiTPP was 1.58 times that of TPP. As a result, it was found that the singlet oxygen generation efficiency was increased by introducing a substituent containing Si into TPP. Specifically, the efficiency of generating singlet oxygen from the excited triplet state of TPP is about 60% to 70%, but it increases to 90% to 100% by introducing the trimethylsilyl group, and the entire light It was found that the sensitization efficiency was improved by 30%.

 In addition, when argon gas (Ar) was injected into the ethanol solution, almost no phosphorescence was generated, confirming that the observed spectrum was due to singlet oxygen.

[0029] The spectrum of singlet oxygen by SiTTP and singlet oxygen by PN were compared by the same method (Fig. 2). As a result, the amount of singlet oxygen by SiTPP was found to be 0.81 times that of PN. The quantum yield Φ for singlet oxygen production by PN has been reported to be 0.94 (J. Phys. Chem., 1995, vol. 99, p9825_9830). From this calculation, it was found that the Φ of SiTTP is 0.77. [0030] Further, a compound in which four trimethylsilyl groups of SiTPP are substituted with -SiMe SiMe is synthesized,

 twenty three

 The spectrum of singlet oxygen of this compound was measured in the same manner as described above. As a result, as shown in Table 1, by introducing the -SiMe SiMe group into TPP, the quantum efficiency is similar to that of SiTPP.

 twenty three

 The increase was about 30%.

[0031] Table 1 summarizes the quantum yield of singlet oxygen generation for each TPP compound.

 [table 1]

[0032] Further, for the Si2TPP and SiTPPS synthesized above, the spectrum of singlet oxygen was measured in the same manner as described above. As a result, the singlet oxygen production efficiencies were 0.76 and 0.69 for Si2TPP and SiTPPS, respectively.

 Industrial applicability

[0033] The compound into which a carbon-containing substituent of the present invention has been introduced can generate singlet oxygen efficiently, and is useful for the treatment of diseases such as cancer. Since the compound of the present invention can be excited even by visible light of 600 to 800 nm, it has an advantage that singlet oxygen can be generated even in a deep part where the penetration distance into the human body is long.

Claims

Claims [1] A singlet oxygen generator comprising one or more compounds selected from the group of compounds represented by the following formulas (i) to (m):  [Chemical 1]

In general formula (I), at least one of R to R is a substituent selected from the following (i) to (iv):  1 14  Yes, in general formula (II), R  At least one of 1 to R is a position selected from the following (i) to (iv):  16  In general formula (III), at least one of R to R is selected from the following (i;) to (iv)  1 12  It is a substituent.  [Chemical 2]

(iv) In the general formulas (i) to (iv), Ra, Rb, and Rc are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, phenyl, methoxy, ethoxy. And a substituent selected from trimethylsilyl.  [2] At least one of R to R other than the substituent selected from the above (i) to (iv) in the general formula (I)  1 14 Is a substituent having so ³ — or COO—, and at least one of R to R other than the substituent selected from the above (i) to (iv) in the general formula (Π) 0 ³ — Or a substituent with COO—  1 16  R other than the substituents selected from the above (i;) to (iv) in the general formula (III)  1 ~ R The singlet oxygen generator according to claim 1, which is a substituent having at least one force of 12 0 ³ — or C00—. [3] A singlet oxygen generator containing one or more compounds represented by the following general formula (ΙΠ): [Chemical 3]

In the general formula (m), at least one of R is a substituent selected from the following (i) to (iv)  1 12  It is.  [Chemical 4] " 1-3 ( _iv )

In the general formulas (i) to (iv), Ra, Rb, and Rc are independently hydrogen, methylol, ethyl, n-propinole, isopropyl, n-butyl, isobutyl, t-butyl, phenyl, methoxy, ethoxy, and trimethylsilyl. It is a substituent selected from more. [4] A small amount of R to R other than the substituent selected from the above (i) to (iv) in the general formula (III)  1 12 4. The singlet oxygen generator according to claim 3, wherein at least one is a substituent having SO ³ — or COO—.  [5] The singlet oxygen generator according to [3], wherein the compound represented by the general formula (III) is a compound represented by the following formulas (IV) to (VII): [Chemical 5] 19

In the general formulas (Vin) to (X), Ra, Rb, and Rc are independently hydrogen, methylol, ethyl, n-propyl, isopropylinole, n-butyl, isobutyl, t-butyl, phenyl, methoxy, ethoxy, It is a substituent selected from trimethylsilyl.