KR100484205B1 - Porphyrin derivatives - Google Patents

Abstract

Provided are phorphyrin derivatives. The phorphyrin derivatives are useful as photosensitizer used in PDT(photodynamic therapy). The phorphyrin derivatives have improved quantum yield producing singlet oxygen, excellent mechanical stability, and improved cytotoxicity compared with photophrin. The phorphyrin derivatives represented by formula (1) or pharmaceutically acceptable salts thereof are provided, wherein R1 is methyl; R2 is triethyleneglycol or methoxytriethyleneglycol; and R3 and R4 independently are hydrogen. The phorphyrin derivatives represented by formula (1) or pharmaceutically acceptable salts thereof are prepared by extracting pheophytin a or 10-hydroxypheophytin a from dried silkworm excreta or green algae by using organic solvent, separating pheophytin a or 10-hydroxypheophytin a through column chromatography or TLC, reacting the separated pheophytin a or 10-hydroxypheophytin a in the presence of acid or base at room temperature or under refluxing condition with methanol to prepare pheophorbide a methylester or 10-hydroxypheophorbide a methylester, and reacting pheophorbide a methylester or 10-hydroxypheophorbide a methylester under nitrogen flow under the dark condition. The phorphyrin derivatives represented by formula (7) or pharmaceutically acceptable salts thereof are provided, wherein R1 is methyl, ethyl or ethyleneglycol.

Description

Porphyrin derivatives {PORPHYRIN DERIVATIVES}

The present invention relates to a porphyrin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, which is useful as a photosensitive material used in photodynamic therapy (PDT).

Formula 1

Wherein R 'is a methyl group, R2 is a triethylene glycol or methoxytriethylene glycol group, and R3 and R' are hydrogen atoms.

Photodynamic therapy is a technique that can treat incurable diseases such as cancer without surgery by using photosensitizer, which is selective and photosensitive to cancer cells or various tumors, and is a kind of radical without the side effects like chemotherapy. It is a law.

By administering the photosensitive material to the subject, for example, by intravenous injection, and irradiating with appropriate light, the excited photosensitive material activates an oxygen molecule to convert it into a singlet oxygen, By creating new radicals or creating new species, selective attack and destruction of only cancer cells or various tumor tissues.

Such photosensitive materials are typical of porphyrin compounds. Porphyrin-based compounds extracted from silkworms, mulberry leaves, and green algae of silkworms have spectroscopic characteristics suitable for use as photosensitive materials. Red light (700-900 nm), which has relatively high cell permeability, is capable of efficiently generating a triplet excited state and a property of causing electron transfer.

Porphyrin derivatives as photosensitive substances are not only selectively penetrated and accumulated in cancer cells or tumor tissues, but also are used as early diagnosis of tumors because they exhibit fluorescence or phosphorescence due to the characteristics of the compounds.

As the porphyrin-related technology, the materials of US Pat. Nos. 5,633,275, 5,654,423, 5,675,001, 5,703,230 and 5,705,622 and US Pat. It is known that it is at various clinical stages. The photoprin II is a mixture of several oligomers in which hematoporphyrin (HpD) is linked by ester bonds.

In addition, BPDMA (verteporphin, WO 97/29915) is a benzoporphyrin derivative, currently known to have a particular effect on skin cancer, psoriasis, and age-related macular degeneration (AMD), and m- has been shown to be useful in the treatment of esophageal and bronchial cancer. THPC (WO 97/48393) or monoastylchlorine (CA 2121716; JP 09071531) are chlorine derivatives, and many of them are registered in the patent file as chlorine derivatives as effective materials for PDT. 97/32885; EP 569113; US Pat.Nos. 5,587,394, 5,648,485, 5,693,632)

Most of these porphyrin compounds are derivatives of meso-tetraphenylporphyrin (TPP) or chlorine, chlorophyll, furfurin, verdin, and Diels-Alder adducts. Aminoleblue acid, phthalocyanine, and the like.

Here, since the yield of producing singlet oxygen molecules is directly related to the cytotoxic effect, the higher the efficiency for the production of singlet oxygen, the more effective cytotoxic effect can be exhibited.

This is a very important factor in photodynamic therapy along with human retention time, and it can be said that there is much room for improvement.

By the way, the photoprint which is currently used clinically as a photosensitive material has a long phototoxicity due to a long residence time of the photosensitive material, and has a lot of quantum yields.

Therefore, in the present invention, to improve the shortcomings of the conventional photosensitive material, as a new modified chlorine-based material obtained through organic synthesis, the quantum yield to produce oxygen in a singlet state is excellent and the physical stability is good, The present invention is to provide a porphyrin derivative or a pharmaceutically acceptable salt thereof that is superior in cytotoxic effect than conventional photoprin.

The present invention relates to a porphyrin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, which is useful as a photosensitive material used in photodynamic therapy (PDT).

Formula 1

Wherein R ', R2, R3 and R' are as defined above, respectively.

In the formula (1) of the present invention, in particular, R ', R2 is a formula, R' is a methyl group, R2 is a triethylene glycol or methoxy triethylene glycol group, R₃ and R 'is preferably a hydrogen atom, the R' and R₃ Are the same as each other, and R2 is not the same as R R or R₃.

Hereinafter, the present invention will be described in more detail through each reaction scheme.

Porphyrin derivatives of the general formula (1) of the present invention, or salts thereof, may be used for the preparation of pheophytin a or 10-hydroxyfepitin a using organic solvents (water, chloroform, alcohol, acetone) Extraction, separation by column chromatography, TLC and the like, which are reacted with methanol at room temperature or under reflux in the presence of an acid or a base to form a pheophorbide a methyl ester or a 10-hydroxyphenophosphide a methyl ester. Then, using this as a starting material, it is obtained by reacting in a blocked state under nitrogen stream.

Scheme 1

                (Formula 2) (Formula 3)

In the formula, R 'represents a diethylene glycol, triethylene glycol or methoxy triethylene glycol group, and R' represents hydrogen.

Purified pheophytin a is reacted at a suitable temperature in the presence of an acid using a conventional alcohol or glycol to remove the solvent, and then the remaining solid is purified by tube chromatography to synthesize a porphyrin derivative. Learn about the specific reaction process through Examples 1-3.

Example 1

Into a 50 mL reaction vessel, add 60 mg of pheophytin a (Formula 2), 3 mL of dichloromethane, and 20 mL of diethylene glycol and stir.

After adding 1 mL of sulfuric acid and stirring for 23 hours, an aqueous sodium hydrogen carbonate solution was added.

After extraction with chloroform and removal of the organic solvent, the remaining solid was separated by column chromatography to obtain 39 mg of the desired compound (Formula 3).

Example 2

In the same manner as in Example 1, 29 mg of the target compound was obtained from 60 mg of pheophytin a and 30 mL of methoxytriethylene glycol.

Example 3

In the same manner as in Example 1, 22 mg of the target compound was obtained from 34 mg of 10-hydroxyphenopytin a and 20 mL of methoxytriethylene glycol.

Scheme 2

             (Formula 4) (Formula 5)

In the above formula, R2 represents bromopropyl, diethylene glycol, triethylene glycol or methoxy triethylene glycol group, and R 'represents hydrogen. The specific reaction process will be described through Examples 4 and 5.

Example 4

Into a 30 mL reaction vessel, 20 mg of methyl pheophobide a methyl ester (Formula 4), 4 mg of pyridine and 8 mL of toluene are added. 0.003mL of 3-bromo-1-propanol was added thereto, followed by heating for 5 hours.

After washing with an aqueous solution of ammonium chloride, extraction with methylene chloride, and then removing the solvent, the remaining material is separated by column chromatography to obtain 11 mg of the target compound (Formula 5).

Example 5

In the same manner as in Example 4, 100 mg of methyl pheophobide a methyl ester, 16 mg of pyridine and 15 mL of toluene were added to a reaction vessel. 0.033 mL of triethylene glycol was added thereto and heated under a nitrogen stream for 16 hours.

After extraction with methylene chloride and removal of the solvent, the remaining material was separated by column chromatography to obtain 73 mg of the target compound.

Scheme 3

                (Formula 6) (Formula 7)

Wherein R 'is methyl or ethyl. The specific reaction process will be described through Example 6.

Example 6

In a 30 mL reaction vessel, 50 mg of methyl pheophobide a methyl ester (Formula 6), 8 mg of pyridine and 23 mg of oxazine are dissolved in 10 mL of toluene and heated for 5 hours.

After washing with an aqueous ammonium chloride solution and extracting with methylene chloride, the solvent was removed and the remaining material was separated by column chromatography to obtain 21 mg of the target compound (Formula 7).

Scheme 4

              (Formula 8) (Formula 9)

In the formula, R 'and R2 are diethylene glycol, triethylene glycol or methoxy triethylene glycol group. The specific reaction process will be described through Example 7.

Example 7

In a 100 mL reaction vessel, 30 mg of the compound of Formula 8 and 20 mL of triethylene glycol were added, and 1 mL of sulfuric acid was added while stirring.

After stirring for 23 hours, the mixture was washed with aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, the solvent was removed, and the remaining material was separated by column chromatography to obtain 32 mg of the target substance (Chemical Formula 9).

Scheme 5

            Formula 10

Wherein R 'is methyl, diethylene glycol, triethylene glycol, and R' is hydrogen. The specific reaction process will be described through Example 8.

Example 8

Dissolve 60 mg of pheophytin a (Formula 10) in a small amount of dichloromethane in a 50 mL reaction vessel, add 20 mL of diethylene glycol and 1 mL of sulfuric acid, and stir for 23 hours. Then, add saturated aqueous sodium hydrogen carbonate solution, Extract.

The solvent was removed and the remaining material was separated by column chromatography to obtain 2 mg of the target material (Formula 11).

As described above, according to the porphyrin derivative or the pharmaceutically acceptable salt thereof of the present invention, which improves the shortcomings of the conventional photosensitive material, the quantum yield to generate oxygen in a singlet state is excellent and physical The stability is good, and the cytotoxic effect is better than that of the existing photoprint, so it can be used and applied in related fields.

Claims (5)

Porphyrin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. Formula 1 delete delete Porphyrin derivatives or pharmaceutically acceptable salts thereof, characterized by the following formula (7) Formula 7 Wherein R 'is a methyl, ethyl or ethylene glycol group. delete