JPS59184181A - 3,8-di(1,2-dihydroxyethyl)deuteroporphyrin - Google Patents

Abstract

NEW MATERIAL:3,8-Di(1,2-dihydroxyethyl)deuteroporphyrin shown by the formula and its salt. USE:Useful as a laser photosensitizer having affinity for tumor. Synthesizable purely and easily. PREPARATION:A protoporphyrin dialkyl ester is reacted with osmium tetroxide to give an addition product, which is hydrolyzed, so that two vinyl group of the protoporphyrin dialkyl ester is converted into a dioxy derivative, which is de- esterifed by hydrolysis, to give a compound shown by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel porphyrin compounds, more specifically, 3,8-di(1,2-dihydroxyethyl) deuteroborphyrin represented by the following formula (1) and salts thereof. Regarding.

In recent years, lasers have been actively applied to medical treatments, and their progress has been particularly remarkable in the treatment and diagnosis of cancer. Among them, Doughert et al. have achieved great results in the early detection and treatment of cancer by combining hematoporphyrin derivatives and argon dye lasers. That is, by utilizing the degree of penetration and orthogonality of the laser into living tissue, a photosensitizer with tumor affinity such as hematoporphyrin derivatives is administered in advance and accumulated in the tumor, and the tumor is stimulated by laser irradiation. In addition to diagnosing the presence or absence of the disease, the site is selectively destroyed by irradiating the affected area with a low-energy argon dye laser.

Treatment of cancer by administering photosensitizers in this way has been carried out in ultraviolet or radiation therapy for a long time, but in recent years, with the advent of lasers, the development of laser photosensitizers with tumor affinity. has been in the spotlight.

D. Kes+sel et al. investigated the tumor affinity and laser photosensitization effect of various porphyrin compounds, and provided hematoporphyrin. However, hematoporphyrin, written by Dolphin, 'Th@Porphyri
ns”,”tlol 1. Launched by Akatemic Press, 1
978, pp. 297-298, it is difficult to obtain a pure product, and the above-mentioned Dough
The one used in the study by etty et al.) is also a mixture of several hematoporphyrin-like substances. This has been a major obstacle in conducting basic research and in applying it to clinical practice.

Therefore, the present inventor conducted intensive research to provide a porphyrin compound that has tumor affinity similar to that of hematoporphyrin and can be easily synthesized in a pure manner, and as a result, completed the present invention.

That is, the present invention provides a 3,8-di(
The present invention provides 1,2-di/-idroxyethyl) deuteroporphyrin and salts thereof.

The os, s-di<1*2-dino-itroxyethyl) deuteroborphyrin (1) of the present invention can be produced, for example, by reacting protoporphyrin dialkyl ester with osmium tetroxide and then hydrolyzing the resulting adduct. It is produced by converting two vinyl groups of a protoporphyrin dialkyl ester into dioxy forms and then de-esterifying it by hydrolysis.

The compound (1) of the present invention obtained in this manner exhibits physical properties similar to those of hematoporphyrin, that is, it exhibits the same solubility in water or buffer solutions, and the same fluorescence intensity is observed when excited at 405 am. . Moreover, as shown in Example 2, the affinity for cancer cells is also equivalent to that of hematoporphyrin.

Next, an explanation will be given with reference to examples.

Example 1 (1) Dissolve 1 t of glotoborophyllin dimethyl ester in 20% of pyridine, and add 30% of diethyl ether to this.
1001111 of a diethyl ether solution of 1 ton of osmium tetroxide is added to the solution under stirring. was added dropwise. The reaction was carried out at room temperature for 1 hour, and the deposited precipitate was collected in a furnace. This is 5
The reaction mixture was dissolved in methanol 1001R1 containing % hydrochloric acid, heated under reflux for 2 hours, and then the reaction solution was filtered, and the filtrate was neutralized with aqueous ammonia. The precipitate was collected in an oven and dried (0.76 F'), dissolved in methylene chloride at warm temperature, and purified by silica gel chromatography to obtain 0.45 t of product. Melting point 228-230°C (decomposition).

As a result of elemental analysis, NMR, and IR analysis, this product was confirmed to be 3,8-di(1,2-dihydroxymethyl) deuteroborphyrin dimethyl ester.

Elemental analysis value: Calculated value %: c 65.64 a H6,43, H8,
jl actual value %: C65,73, H6,40, H8,5
5IH-NMR (10% solution of ds-pyridine) δ3.
40 (4H, m, 13-I Chz117-I C
H2), 3-50 (6H=m, 18C)Ig
, 12 C) Is ), 3.58 (6H, l l 7C
H3), 3.68 (3HI I # 2CHa),
3,80 (3H+a+7CH3),4.8
(2Ht m + 3-158-ICH), 5. I
C2H, m, 8-2CH2), 5.2 (2H, a, 3-
2CH2), 6.9 (4n, b, -on), 10.30
(IH, s, 150H), 10.47(1) I, a.

20 CH), 11.18 (in, s -10cH)
, 11-23 (in, s, 5CH).

(i) 0.3f' of dimethyl ester obtained in above)
The mixture was dissolved in 100% of pyridine, added with a methanol solution of 45 μm of caustic soda, and stirred at 70° C. for 2 hours. After the reaction,
The precipitated crystals were collected in a furnace, washed successively with pyridine, dichloroethane, and acetone, and then dried to obtain 0.3f of 3,8-di(1,2-dihydroxyethyl) deuterophorphyrin disodium.

UV spectrum H9 λ nm (emM): 395 (148,43), so
sm&X (5,60), 539 (3,91), 565 (3,37
)615(1,42).

11N-H2s0' nm (smM): 403 (33
0,60), 550 (1187), 592 (4,31)
.

Example 2 A cultured cell line (JTC-16) derived from DAB-induced rat ascites liver cancer (AH-7974) was cultured in DM-170 medium at 37°C, and in the mid-logarithmic growth phase, hematoporphyrin (HPD) or 3°C 8-di(1,2-dihydroxyethyl) deuteroborphyrin disodium (0
HDP Na2) was added and after incubation for 24 hours, the energy of 5 mW/cm2 was applied at wavelength 48.
It was irradiated with an 8 nm argon laser.

As a result, no change was observed in the additive-free cells after 3 minutes of laser irradiation. In the case of HPD, there was no change even if the cells were incubated at a concentration of 15 μt/lnt without laser irradiation, but when laser irradiation was performed for 1 minute, the cells changed. In the case of 0HDPNa*, there was no change in the incubation temperature without irradiation with the 20 μt/-humidity telelaser, but there was a change in the 11kK cells exposed to the laser.

From the above results, the affinity for cancer cells is HPD and 0H.
tl was comparable in DPNa2.

Claims (1)

[Claims] 3,8-di(1,2-dinoidroxyethyl)deuteroporphyrin and its salt.