JPS62167783A - Porphyrin derivative - Google Patents

Abstract

NEW MATERIAL:A porphyrin derivative expressed by formula I (R1 is H, alkyl or ethenyl; R2 is O(CmH2m)N(A)B, S(CmH2m)N(A)B, O(CH2CH2O)nH or S(CH2CH2 S)nH (A and B are alkyl; m is 1-23; n is 1-4), etc.]. EXAMPLE:7,12-Diethenyl-3,8,13,17-tetramethyl-2, 18-bis[2-(2-dimethylaminoethyloxy) carbonylethyl]-21H,23H-porphyrin. USE:A diagnostic and treating agent for cancer, capable of chemically modifying propionic acid groups at the 2,18-positions or ethenyl groups at the 7,12-positions of porphyrin and having photosensitizing action and affinity for cancerous cells. PREPARATION:For example, a porphyrin derivative expressed by formula II (X is halogen) is condensed with a compound expressed by formula III, IV, V etc., or a salt thereof, etc., to afford part of the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides novel porphyrin derivatives for use in the diagnosis and treatment of cancer.

BACKGROUND OF THE INVENTION Recently, porphyrin derivatives that have an affinity for cancer cells and have a photosensitizing effect have been used in combination with laser light irradiation to achieve success in the diagnosis and treatment of cancer. (T,
J. Doughherty, “Porphyrin Lo
Calization and Treatment
of Tumors”, pp. 75-78 (1984
)) Hematoporphyrin or hematoporphyrin derivatives are mainly used for this purpose, but the former is difficult to obtain in pure form [K., Di.
Ne1lo et al.”The Porphyrins”Vo
1, pp. 1, 297-298 (1978)); the latter is acetylated and then treated with alkali and acid, and contains dozens of porphyrin derivatives.

It is said that such hematoporphyrin has major problems in clinical application.

Problems to be resolved by the invention Currently, as mentioned above, only a few dozen types of hematoporphyrin derivatives are available as a mixture for use in the diagnosis and treatment of cancer. Since it is difficult to obtain high-quality products, this poses a major hindrance to testing for medicinal efficacy or toxicity. In order to solve this problem, it is important to obtain a compound that is a pure porphyrin derivative and has both photosensitizing action and affinity for cancer cells.

Means for Solving the Problem The present inventors chemically modified the propionic acid group at the 2.18-position of porphyrin, represented by 000HC00H (wherein 1 represents a hydrogen atom, a lower alkyl group, or a vinyl group). As a result, various porphyrin derivatives having photosensitizing action and affinity for cancer cells were synthesized and the present invention was completed.

The porphyrin derivative obtained here has (in the general formula k, RL has the same meaning as above; R2 represents an integer of 1 to 23, and n represents an integer of 1 to 4), or a benzyloxy group, a benzylthio group, or a benzylamino group. and these may have substituents). In the formula, the lower alkyl groups represented by A, B and C are preferably methyl and ethyl.

C1-C4 alkyl such as propyl and butyl.

The porphyrin represented by
20H2S) nHC In the formula, A, B, m, n are the same as above @) or a salt thereof, or a condensation reaction with benzyl alcohol, thiobenzyl alcohol or benzyl amine which may have a substituent. By doing this, in the porphyrin derivative represented by general formula (1), rL2 becomes O(Cm R2m ) N <B
, O((:! H20H20) n H or S (C
A porphyrin derivative showing I(2CI(28)nH, or a benzyloxy group, benzylthio group, or benzylamino group which may have a substituent) is obtained.The solvent used for this condensation reaction is methylene chloride, chloroform. , ethyl acetate, etc., but methylene chloride is usually preferred. Examples of acid scavengers include triethylamine, pyridine, quinoline, etc., but triethylamine is preferred. The reaction temperature and reaction time are adjusted as appropriate. Usually, the reaction is completed in 0.5 to 5 hours at O''C to 100°C.For example, when methylene chloride is used as the solvent, the reaction is completed at 1 to 100℃ at the reflux temperature of methylene chloride.
The condensation reaction cannot be completed within 2 hours, and the porphyrin derivative is reacted with a lower alkyl halide in the presence or absence of a solvent to convert it into a quaternary ammonium salt. Preferred solvents used in this reaction include:
Examples include methylene chloride, chloroform, and ethylene dichloride.

The reaction temperature and reaction time can be selected as appropriate, for example, 0°C.
The reaction is completed in 5 minutes to 5 hours at ~100°C, but can usually be completed in 0.5 to 1 hour at 20°C to 30°C. Post-reaction treatment and purification of these novel porphyrin derivatives can be carried out by conventional methods, e.g. extraction,
This is carried out by recrystallization, column chromatography, activated carbon treatment, etc.

Hereinafter, it will be explained in more detail using examples.

Reference example 1 7.12-jethinyl-3,8,13,17-titramethyl-211-1.23 H-porphine-2,18-
Synthesis of dipropionic acid chloride 7. Suspend 1y of 12-jethynyl-3,8,13,17-tetramethyl-2LH,23H-porphine-2,18-dipropionic acid in 35yttt of methylene chloride,
Oxalyl chloride 2.5- was added dropwise under reflux, and after refluxing for 15 minutes, the solvent was distilled off under reduced pressure to form a residue of 7,12-jethinyl-3゜8.11,1.
7-thitramethyl-211-1.23H-porphine-
1.11 of 2,18-dipropionic acid chloride was obtained.

Example 1 Synthesis of 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-21H023)1-porphine 7.12 - Jetinyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropionic acid chloride (1.199 g) was added to 60 tons of methylene chloride, and 2-dimethylaminoethanol was added to 5 g of 2-dimethylaminoethanol under reflux.
ml and refluxed for 45 minutes, further added 2-dimethylaminoethanol for 5 minutes, stopped refluxing for 45 minutes, and then distilled the solvent off under reduced pressure.
Add pal and dissolve, wash with Loom water, and concentrate the chloroform layer to dryness under reduced pressure. This was concentrated to dryness, and the alumina (activity Y
) Purified by column chromatography using 100 g of 7,12-jethynyl-3,8゜13.17-tetramethyl-2,18-bisC2-C2-dimethylaminoethyloxy) as a packing material. Crystals of (carbonylethyl) -21H,23FI-porphine were obtained.

Melting point 187-191℃ Visible absorption maximum (in chloroform) 407.506,541,577.630 (n77i1
) Infrared absorption spectrum (KBr) 3305.2960, 2940, 2900, 2850° 2810.2760, 1785 ((,M) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ: 9.70.9
．． 56.9.49 (s, 2H, LH, 1l-I)8
．． 10-7.72 (m, 2H) 6.24-5.92 (m, 4H) 4.26 (t, 41~■) 4.15 (t, 4H) 3.4.4.3.38. 8!6.3.34 (s, 3
Hx4) 8.19 (t, 4H) 2.36 (t, 41-I) 2゜06
(S, 12H) -4,48(s, 2H) Example 2 7.12-jethynyl-8,8,18,17-tetramethyl-2,18-bis(2-(1,8-bis(dimethyl amino)-2-propyloxy)carbonylethyl)-
Synthesis of 21H,23H-porphine 7,12-jethynyl-3,8,13,17-
Citramethyl-21H,23n-1 Rufin-2,1
8-Dipropionic acid chloride 1.11 and 1,3-bis(dimethylamino)-2-propatool 5at were condensed to give 480 M9 dark brown 7,12-jethynyl-3,8,13,17- Tetramethyl-2,18-bis(2(1,8-bis(dimethylamino)-2-propyloxy)carbonylethyl, l-21H,23H-porphine was obtained.

Melting point 181-190°C Visible absorption maximum (in chloroform) 407.5.505.5.541.576, 630.5
Cnyn) Infrared absorption spectrum (KBr) 3305, 2960. 2930. 2900. 2
850°2810,2760.1730 (cll
) Nuclear magnetic resonance spectrum (in deuterated chloroform) δ; 9.
79.9.76, 9.56 (S, IHX4) 8.1
4-7.76 (m, 2H) 6.24-5.92 (m, 4H) 5.13 (t, 2H) 4.82 (t, 4H) 3.48.3.44.3.39 ( s, 3H, 3H,
6H) 3.21 (t, 4M) 2.21 (d, 8H) 2.04 (S, 24H) -4,32(S, 2H) Example 3 7.12-jethynyl-3,8,18, 17-tetramethyl-2,18-bis(2-(6-dimethylamine-1
-hexyloxy)carbonylethyl)-21H,23
Synthesis of H-porphine The same operation as in Example 1 was performed to obtain 7,12-jethynyl-3,8,13,17-titramethyl-2LH.

28H-porphine-2,18-dipropionic acid chloride 1.11 is condensed with 6-dimethylamino-1-hexanol 5-shoulder t to give 450 M9 dark brown 7°12
-jetinyl-3,8,13,17-tetramethyl-2
, 18-bis(2-(6-dimethylamino-1-hexyloxy)carbonylethyl)-2LH.

Crystals of 23H-porphine were obtained.

Melting point 160-165°C Visible absorption maximum (in chloroform) 407.5.505.5.541.576, 630.5
(72m) Infrared absorption spectrum (KBr) 8300.2920, 2850, 2800, 2750° 1715 (clll) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.7
．． 9.6.9-52 (S, 2H, LH, LH)8.
2- T, T (broad 2H) 6.28-5.9
(m, 4H) 4.27 (t, 4) I) 4.02 (t, 4H) 3.42.3.38 (S, 6H, 6H) 3.16
(t, 4H) 2.02 (s, 12H) 2 - 1.8 (m, 4H) 1.5-1.2 (m, 4H) 1.2-0.9 (m, 16H) -4, 6 (broad, 2H) Example 4 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bisC2-(N-(2-dimethylaminoethyl)carbamoyl)ethyl)-21H, 23H-
Synthesis of porphine Performing the same operation as in Example 1, 7,12-jethinyl-3,8,1:13.17-titramethyl-2 L H
.

23H-porphine-2,18-dipropionic acid chloride 1.1y to 2-dimethylaminoethylamine 5t
Condensation with ttt gives 7401'9 dark brown 7,12
-jetinyl-3,8,13,17-titramethyl-2
Crystals of 18-bis(2-(N-(2-dimethylaminoethyl)carbamoyl)ethyl)-21H,23H-porphine were obtained.

Melting point 300°C or higher Visible absorption maximum (in chloroform) 406.5, 506, 541, 576.630 (nm)
Infrared absorption spectrum (KBr) 3290.2925, 2850, 2805, 2750° 1640 (ff) Nuclear magnetic resonance spectrum (in deuterochloroform) δ; 9.
44.9.39.9.34.9.19 (S, IHX
4) 8.06-7.62 (m, 2H) 6.8-6.6 (m, 2H) 6.21-5.88 (m, 4l-I) 4,02
(broad, 4 H) 3.28.3.26.
3.24.3.15 (s, 3Hx4)j, o 4
-2.76 (m, 4HX2) 1.76.1.73
(t, 21(x 2 )1.57.1.53 (s
, 6f(x2)-5,05(S, 2f-I) Example 5 7.12-jetinyl-3,8,13,17-tetramethyl-2,18-bis(2-(N-(3- dimethylaminopropyl)carbamoyl)ethyl)-2LH, 23H
-Synthesis of porphine The same operation as in Example 1 was performed to obtain 7,12-jethynyl-3,8,13,17-titramethyl-2LH.

231■-Porphine-2,18-dipropionic acid chloride 1.1y and 3-dimethylaminopropylamine 5
ml and condensed to give 650 ~ dark brown 7,12-jethynyl-3,8,13,17-titramethyl-2゜1
8-bisC2-(N-(3-dimethylaminopropyl)
Crystals of (carbamoyl)ethyl)-21H,28H-porphine were obtained.

Melting point 300°C or higher Visible absorption maximum (in chloroform) 407.505.5, 541, 576, 630 (nm)
Infrared absorption spectrum (KBr) 3800.8075, 2920, 2850, 2800° 2750.1640 (bacteria) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.5
3.9.39.9.28 (s, 2H, IH, LH)8
．． 09-7.65 (m, 2H) 7.55-7.35 (m, 2H) 6.23-5.88 (m, 4H) 4.05 (t, 4H) 3.33, 3.28, 8.27, 3.12 (S, 3H
X4) 2.92 (t, 4H) 2.85 (t, 4H) 1.66-1.5 (t, 4H) 1.63, 1.59 (S, 6HX2) 1.11
(q, 4H) -4,88(s, 2H) Reference example 2 8,8.13.17-tetramethyl-2LH,23H-
Synthesis of porphine-2,18-dipropionic acid chloride 3, 8.13.17-tetramethyl-21H,23H-
Porphyne-2,18-dipropionic acid 1y is suspended in 85 tptl of methylene chloride, 2.5 txl of oxalyl chloride is added dropwise under reflux, and reflux is continued for 15 minutes to complete the reaction. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was 3.8.13.17-tetramethyl-21H,2
1.11 of 3H-porphyne-2,18-dipropionic acid chloride was obtained.

Example 6 3,8.13.17-tetramethyl-2,18-bis(
Synthesis of 2-(2-dimethylaminoethyloxy)carbonylethyl)-21H,23H-porphine.

3,8.13.17-titramethyl-211(,23H
-Porphine-2,18-dipropionic acid chloride 1
．． 1 g was added to 60 ml of methylene chloride, and under reflux, 5 tttl of 2-dimethylaminoethanol was added.
After refluxing for 5 minutes, 2-dimethylaminoethanol 5
ml and refluxed for another 45 minutes, the solvent was distilled off under reduced pressure, the residue was dissolved in 100 ml of chloroform, washed with 100 ml of water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was purified by column chromatography using chloroform as a solvent and alumina (activity ■) as a packing material of 100 dah to give a blackish brown crystal of 3.8.13° 17-tetramethyl-2,
18-bis(2-(2-dimethylaminoethyloxy)
Carbonylethyl)-211-1,23H-porphine 330#f was obtained.

Melting point 159-161°C Visible absorption maximum (in chloroform) 899.496.5, 529.5, 566.591.5
゜619 (nm) Infrared absorption spectrum (KBr) 3300.2925, 2845, 2805, 2755゜Nuclear magnetic resonance spectrum (in deuterated chloroform) δ; 9. '
77, 9.68.9.67 (s, IH, IH, 2H
)8.76.8.75 (S, IHX2) 4.25 (t, 4H) 4.12 (t, 4I-f) 3.56.148.3.44.3.39 (s, 3H
x4 ) 3.10 (t, 4l-I) 2.32 (t, 4H) 2.04 (s, 6H) -4,31(s, 2l-I) Reference Example 3 7.12-diethyl-8, Synthesis of 8,18,17-tetramethyl-21H,23H-porphine-2,18-dipropionic acid chloride.

7. 1 g of 12-diethyl-8,8,13,17-tetramethyl-2LH,23H-porphine-2,18-dipropionic acid is suspended in 35 liters of methylene chloride, and oxalyl chloride 2. 5 tel dripping 1
The reaction is completed by refluxing for 5 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and 1.1 g of 7.12-diethyl-
3,8,13,17-thitramethyl-21H,2(H-
Porphine-2,18-dipropionic acid chloride was obtained.

Example 7 7. Synthesis of 28H-porphine in 12-diethyl-8,8,18,17-tetramethyl-2,18-bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-21.

7. To 1.11 of 12-diethyl-3,8,18,17-tetramethyl-21H,23H-porphine-2,18-dipropionic acid chloride was added 60zt of methylene chloride, and under reflux, 2-dimethylaminoethanol was added. After adding 5 ml of 2-dimethylaminoethanol and refluxing for 45 minutes, the solvent was distilled off under reduced pressure, and the residue was diluted with 10 ml of chloroform.
Add 0*t to dissolve and wash with water. The chloroform layer was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography using 100f alumina (activity V) as a packing material and chloroform as a solvent to obtain 9801'l.
(7゜12-diethyl-3,8,13,17-titramethyl-2.18-bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-21) 1.28H
- Dark brown crystals of porphine were obtained.

Melting point 168-172°C Visible absorption maximum (in chloroform) 839.5,498,582,567.59 & 5°62
0.5 (nm) Infrared absorption spectrum (KBr) 8305.2955.29B0,2855,2810°2710,17:l15 (011) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.9
2,9,87,9.83,9-81(s,IHX4)4
．． 85.4.82 (t, 2Hx2) 4.13
(t, 4H) 3.94.3.91 (q, 2HX2) 3.56.
3.50.3.44 (S, 8H, 6H, 3H)3.
25 (t, 4H) 2.33 (t, 4H) 2.02 (s, 6H) 1.78.177 (t, 2)tX2)-a, 92
<s, 2H) Example 8 7.12-jethynyl-3,8,18,17-tetramethyl-2,18-bis(2-(2-1limethylammonioethyloxy)carbonylethyl)-211- 1,2
Synthesis of 3H-porphine diiodide.

7,12-jethynyl-3,8,13゜17-tetramethyl-2,18-bis(2-(2-dimethylaminoetheloxy)carbonylethyl)-21H obtained in Example 1
, 28H-Porfin 100#! methylene chloride 10
1261119, 7,12-jethynyl-8,8,18,17-tetramethyl-2,18-bis(2-(2 -trimethylammonioethyloxy)carbonylethyl)-2LH, 28, blackish brown crystals of monoporphine diaiodide were obtained.

Visible absorption maximum (underwater) 676.512,548,576.5,630.5 C
nm) Infrared absorption spectrum (KBr) 8300.2900.1725 (cIR) Nuclear magnetic resonance spectrum (DMSO-dr, medium) δ; 9.74.9.
66 (S, 2I-IX2)8.4-7.8 (
m, 2H) 6.4-6.0 (m, 4H) 4.5-4.0 (broad, 4HX2)8.
48 (S, 3Hx4) 8.26 (broad, 4Hx2) 2.7
9 (S, 18H) -5,08(broad, 2H) Example 9 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-((1,3-bis -Trimethylammonio)-2-propyloxy)carbonylethyl)-21H,23H-Porphine tetraiodide Synthesis of 7,12-jethynyl-3,8゜18.
17-tetramethyl-2,18-bis(2-(1゜3-
Bis-(dimethylamino)-2-propyloxy)carbonylethyl)-21H,23H-porphine 100q
was dissolved in 10 g of methylene chloride, and 111 g of methyl iodide was added.
The number of crystals precipitated by adding t is 7,1 of 10019.
2-jethinyl-8,8,18,17-tetramethyl-
2,18-bis(2-((1,3-bis-trimethylammonio)-2-propyloxy)carbonylethyl)
Dark brown crystals of -21H,23H-porphine tetraiodide were obtained.

Visible absorption maximum (underwater) 398, 509.543.5.573.5.628.5
(im) Infrared absorption spectrum (KBr) 8300.2995.2980, 2850°1740
(α) Nuclear magnetic resonance spectrum (in CDMSO-d6) δ; 10
．． 20-9.96 (S, HIX4) 8.52-8
．． 02 (m, 2H) 6.44-6.06 (m, 4H) 5.88-5.58 (broad, 2H) 4.68
-4.28 (broad, 4H) 196-8.4
(m, 4H, 4H, 4H) 164-8.56 (s,
3Hx4) 3.08 (S, 36H) -4,26(broad, 2H) Example 10 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-(N- (2-)limethylammonioethyl)carbamoyl)ethyl]-211(,
Synthesis of 23H-porphyndiaiodide 7,12-jethynyl-3,8,13゜17-tetramethyl-2,18-bis(2-(N-(2
-dimethylaminoethyl)carbamoyl)ethylcou 2
1H,28H-porphine 100q with methylene chloride 20
After heating and dissolving Mt, return to room temperature and add 1 ml of methyl iodide to precipitate crystals, totaling 127q.
,12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-(N-(2-trimethylammonioethyl)carbamoyl)ethyl)-2LH,23
Dark brown crystals of H-porphyndiaiodide were obtained.

Visible absorption maximum (underwater) 377.5, 510, 548, 575.5, 630 (f
fm) Infrared absorption spectrum (KBr) 3300.3230,2900,2845°1655(
clR) Nuclear magnetic resonance spectrum (DMSO-(in 16) δ; 1
0.2-10.05 (S,lllX4)8.6-
8.0 (m, 2H) 6.6-6.0 (m-, 4H) 4.87 (t, 4H) 18-3.6 (m, 8f() 3.28 (broad, 3Hx4)3. 14
(t, 4H) 2.54 (S, 18H) Example 11 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-(N-(3-trimethylammonio) propyl)carbamoyl)ethylcou 2-LH
, 23H-Porphindiaiodide Synthesis Example 5 7,12-jethynyl-a, s, t
a.

17-tetramethyl-2,18-bis(2-(N-(3
-dimethylaminopropyl)carbamoyl)ethyl)-
2LH, 23H-po, 11/fin 100119 with salt (
16 Dissolved in methylene 10m/methyl iodide l tr
The number of crystals precipitated by adding tl is 7,1 of 126q.
2-jethynyl-3,8,1:9.17-tetramethyl-2,18-bis(2-(N-(8-trimethylammoniopropyl)carbamoyl)ethyl, 1)-21H,
Dark brown crystals of 23H-porphyndiaiodide were obtained.

Visible absorption maximum (underwater) 380.5. 510. 546, 577, 631
(nm>Infrared absorption spectrum (KBr) 3800.3250,2900,2850°1640
(α) Nuclear magnetic resonance spectrum (in DMSO-46) δ; 9.9
4.9.86.9.78 (S, 11-I, LH,
2H) 8.5-8.06 (m, 2fI) 8.02-7.86 (m, 2H) 6.4-6.09 (m, 4H) 4.3 (broad, 4H) 154
(broad, 12H)8.1-2.8 (br
oad, 8H) 2.62 (broad, 4
H) 1.3 (broad, 4H)-4,9
(broad, 2H) Example 12 Synthesis of 7.12-jethynyl-8,8,13,17-tetramethyl-2,18-bis(2-(2-hydroxyethyloxy)carbonylethyl-21H,23H-porphine) The same operation as in Example 1 was performed to obtain 7,12-jethynyl-3,8,13,17-tetramethyl-21H628H.
-Porphine-2,18-dipropionic acid chloride 1
．． 1g is condensed with 1,2-ethanediol 5yst to give 450 ~ dark brown 7,12-jethynyl-3,8
,13,17-tetramethyl-2,18-bis(2-(
2-hydroxyethyloxy)carbonylethyl-21
Crystals of H,28H-porphine were obtained.

Visible absorption spectrum (in chloroform) 406.5.
505.5.541.5.575.5.630 (nm)
Infrared absorption spectrum (KBr) 8390.8300,2900,2850°1735(
crll) Nuclear magnetic resonance spectrum (in CF8CO2D) δ; 8.3
6-8.0 Cm, 2H) 6.61-6.22 (m
, 4H) 4.8-4.5 (m, 12H) 3.81.8.79.3.75 (S, 3H, 6H,
3H) 3.27 (t, 4H) Example 13 7.12-jethynyl-3,8,18,17-tetramethyl-2,18-bis(2-(benzyloxy)carbonylethyl)-2LH,23I( - Synthesis of porphine By performing the same operation as in Example 1, 7,12-jethinyl-3,8,18,17-titramethyl-21H023H
-Porphine-2,18-dipropionic acid chloride 1
．． 690 by condensing 11 and benzyl alcohol 5-resistant
Mg dark brown 7,12-jetinyl-3°8.13.
17-tetramethyl-2,18-bis(2-(benzyloxy)carbonylethyl)-21H.

Crystals of 23H-porphine were obtained.

Melting point: 185-189°C Maximum absorption in chloroform (in chloroform): 408.505.5, 541, 576.680 Cnm)
Infrared absorption spectrum (KBr) 3800.8080, 3050, 8020, 2400° 2850.1735 (CrII) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.6
0.9.56.9.52.9.86 (S, 1flX
4) 8.09-7.70 (m, 2H) 6.98 (s, 10H) 6.22-5.90 (m, 4H) 4.99 (s, 4H) 4.16 (t, 4) f) 3.32, 8.24 (S, 8H x 8, 8H) 3.15
(t, 4H) -4,66(s, 2H) Example 14 7.12-jethinyl-3,8,13,17-tetramethyl-2,18-bis(2-(P-nitrobenzyloxy)carbonyl Synthesis of 7,12-jethynyl-3,8,13,17-tetramethyl-21H023H
-Porphine-2,18-dipropionic acid chloride 1
．． 1 g of P-nitrobenzyl alcohol and 5 ml of P-nitrobenzyl alcohol were condensed to give 720''f/dark brown 7,12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-(P-nitrobenzyl) Crystals of benzyloxy)carbonylethyl)-21H,28H-porphine were obtained.

Melting point 191-195°C Visible absorption maximum (in chloroform) 408.506,541,576.630 (7 gm) Infrared absorption spectrum (KBr) 3800.3070, 2900, 2850, 1740° 1520.1345 (ff) Nucleus Magnetic resonance spectrum (CDC18-CF3 C!02
D) δ; 10.74.10.56.10.4.9(
s, IH, IH, 2H) 8.19-7.9 (m,
2H) 7.92.7.20 (d, 4HX2) 6.40-
6.10 (m, 4H) 4.96 (s, 4H) 3.65.3.61.3.56.8.54 (S, 8
HX4 ) 2.10 (t, 4H) Example 15 7.12-jethynyl-3,8,18,17-tetramethyl-2,18-bis(2-(2-mercaptoethylthio)carbonylethyl)-21H , 2BH-Porphine The same procedure as in Example 1 was carried out to obtain 7,12-jethynyl-3,8,13,17-titramethyl-2LH.

23I (-porphine-2,18-dipropionic acid chloride 1.1 f/ and 1,2-ethanedithiol 5 t
ttt to give 320 Mf) blackish brown 7,1
2-jethynyl-3', 8.18.17-tetramethyl-2,18-bis(2-(2-mercaptoethylthio)carbonylethyl)-211(,23H-porphine) was obtained.

Visible absorption maximum (in chloroform) 407.5.507.540.5.576.5.680
(nm) Infrared absorption spectrum (KBr) 8800.2900,2840,2540°1690(
cNl) Nuclear magnetic resonance spectrum (in OFaCO2D) δ; 10
．． 52.10.45. IQ, 42. l0JI(s,
IHX4) 7.9-7. ．． 4 (m, 2H) 6.1-5.7 (m, 4H) 4, 1 (broad, 4iJn)8.
81 (broad, 8H) 128
(S, 12H) 2.8 (broad, 4H) Example 16 7.12-jethynyl-s, s, ta, 17-tetramethyl-2,18-bis(2-(benzylthio)carbonylethyl)-2LH, Synthesis of 23H-porphine The same operation as in Example 1 was performed to obtain 7,12-jethynyl-3,8,13,17-tetramethyl-21H023H.
-Porphine-2,18-dipropionic acid chloride 1
．． 1 g of thiobenzyl alcohol and 5 Mt of thiobenzyl alcohol to give 51,011 fl of dark brown 7,12-jethynyl-8,8,18,17-tetramethyl-2,18-bis(2-(benzylthio)carbonylethyl)- 2LH
, 23H-porphine crystals were obtained.

Melting point 116-122°C Infrared absorption spectrum (KBr) 3300.8050, 8015, 2990, 2950° 2900.2850, 2800, 1680 (CIR)
Nuclear magnetic resonance spectrum (in deuterated chloroform) δ; 10.
64, 10.46, 10.42, 10J4(s, IHX
4) 8.3 - 7.7 (m, 2H) 7.1
4 (S, l0H) 6.4- 6.1
(m, 4H) 4.4 - 4.2 (bro
ad, 4H) 4.08 (S, 4H) 156.3.46 (s, 6H, 6H) 3.42
(t, 4H) -L, 5--1.8 (broad, 2H) Effects of the Invention The compounds of the present invention are deutroporphyrin LX and mesoporphyrin LX according to the Hirascher nomenclature.

It is a pure porphyrin derivative synthesized using protoporphyrin IX.

In addition, each of these porphyrin derivatives has the ability to accumulate in cancer cells, emit fluorescence when irradiated with light, and generate '02 when irradiated with light in the presence of oxygen, and this '02 Since it has the effect of killing cancer, it is useful as a diagnostic and therapeutic agent for cancer.

Procedures Written amendment (voluntary) January 22, 1988 Patent Application No. 8789 of 1988 2, Name of the invention Porphyrin derivative 3, Relationship with the person making the amendment Patent applicant 4, Agent address: 541 Mansei Building, 4-46 Kitahama, Higashi-ku, Osaka City Name (6249) Inclination Takashi'・)5 Telephone Osaka (
06) 202-5858 (representative) details
Book 1, Title of the Invention Porphyrin Derivatives 2, Claims (1) General Formula [In the above general formula, l1m is a hydrogen atom, a lower alkyl group, each lower alkyl group, X is) 10 gene atoms, m is 1 to 2
3, n represents an integer of 1 to 4), or a benzyloxy group, a benzylthio group, or a benzylamino group,
They may have a substituent.

(2) General formula (In the above general formula, R1 is a hydrogen atom, a lower alkyl group, or
This is an ethynyl group; X represents a halogen atom. ) is a porphyrin derivative represented by the general formula % formula %) (wherein A and E are each a lower alkyl group, m is 1 to 2
3, n represents an integer of 1 to 4) or a salt thereof, or benzyl alcohol, thiobenzyl alcohol, or benzyl amine which may have a substituent. CH20H2S)HH (A and B are each a lower alkyl group, m is an integer of 1 to 23, n is an integer of 1 to 4), or a benzyloxy group, a benzylthio group, or a benzylamino group, which has a substituent. A method for producing a porphyrin derivative represented by

(3) General formula [In the above general formula, R1 has the same meaning as above; R4 is middle, m is 1
-23 integers, A and B each represent a lower alkyl group] is reacted with a halogenated lower alkyl group, each of which is a lower alkyl group, and X is a halogen. Atom, m is 1-2
A method for producing a porphyrin derivative represented by n].

3. Detailed Description of the Invention Industrial Application Field The present invention provides a novel porphyrin derivative for use in the diagnosis and treatment of cancer.

BACKGROUND OF THE INVENTION Recently, porphyrin derivatives that have an affinity for cancer cells and have a photosensitizing effect have been used in combination with laser light irradiation to achieve success in the diagnosis and treatment of cancer. (T,
J. Doughherty, “Porphyrin Lo
Calization and Treatment
of Tumors, pp. 75-78 (1984)) Hematoporphyrin or hematoporphyrin derivatives are mainly used, but the former is difficult to obtain in a pure form (R, K, Di Ne1
lo et al. “The Porphyrins Vol.1.1”
297. 298 (1978)), the latter is obtained by acetylating the former and then treating it with alkali and acid, and contains several dozen types of porphyrin derivatives. It is said that such hematoporphyrin has major problems in clinical application.

Problems to be Solved by the Invention As mentioned above, only a few dozen types of hematoporphyrin derivatives, which are currently being used in the diagnosis and treatment of cancer, can be obtained as a mixture. Since it is difficult to obtain high-quality products, it is a major hindrance to testing for medicinal efficacy or toxicity. In order to solve this problem, it is important to obtain a compound that is a pure porphyrin derivative and has both photosensitizing action and affinity for cancer cells.

Means for Solving the Problems The present inventors have developed a porphyrin 2.18 represented by the general formula (in the formula, each represents a hydrogen atom and each lower alkyl group represents an ethynyl group).
The present invention was completed by synthesizing various vorufirin derivatives having photosensitizing action and affinity for cancer cells by chemically modifying the propionic acid group at position 1 or the ethynyl group at position 7 and 12, 0 here (the resulting porphyrin derivative has the general formula [in the above general formula, R1 has the same meaning as above; 几2 is 1-23,
n represents an integer of 1 to 4), or a benzyloxy group, benzylthio group, or benzylamino group, which may have a substituent. In the formula, A,
The lower alkyl group represented by B and C is preferably C1-C4 alkyl such as methyl, ethyl, propyl, butyl. These porphyrin derivatives are produced by halogenating the porphyrin represented by the general formula (n), and dissolving the acid halide in the presence of an acid scavenger or non-H8 (0H
20H2S ) nH (wherein A, B, m, n are the same as above) or a salt thereof, or a condensation reaction with benzyl alcohol, thiobenzyl alcohol or benzyl amine which may have a substituent. By doing this, in the porphyrin derivative represented by the general formula (1) where n is 0 (OH20H20)HH or S (0H20H2S)nH, or a benzyloxy group which may have a substituent, a benzylthio group, A porphyrin derivative exhibiting benzylamino groups is obtained. Examples of the solvent used in this condensation reaction include methylene chloride, chloroform, and ethyl acetate, but methylene chloride and lene are usually preferably used. Examples of the acid scavenger include triethylamine, pyridine, and quinoline, but triethylamine is preferably used. The reaction temperature and reaction time can be selected as appropriate. Usually 0°C to 100°C
．． The reaction is completed in 5 to 5 hours.

For example, when methylene chloride is used as a solvent, the condensation reaction can be completed in 1 to 2 hours at the reflux temperature of methylene chloride. It can also be expressed by the general formula (1). A porphyrin derivative represented by the general formula (1) is converted into a quaternary ammonium salt by reacting with a lower alkyl halide in the presence or absence of a solvent. Preferred solvents used in this reaction include methylene chloride, chloroform, ethylene dichloride, and the like.

The reaction temperature and reaction time can be selected as appropriate, for example, 0°C.
The reaction is completed in 5 minutes to 5 hours at ~100°C, but can usually be completed in 0.5 to 1 hour at 20°C to 30°C. Post-reaction treatment and purification of these novel porphyrin derivatives can be carried out by conventional methods, e.g. extraction,
This is carried out by recrystallization, column chromatography, activated carbon treatment, etc.

Hereinafter, it will be explained in more detail using examples.

Reference Example 1 7.12-jethinyl-3,8,13,17-titramethyl-21f (,23H-porphine-2,18-dipropionic acid chloride synthesis 7, I2-jethynyl-3,8,13,17-titramethyl 1 g of -211, 23H-porphine-2,18-dipropionic acid was suspended in 85 ytt of methylene chloride,
Oxalyl chloride 2.5 rttl under reflux
was added dropwise, and after refluxing for 15 minutes, the solvent was distilled off under reduced pressure, leaving a residue of 7,12-jethinyl-8,8,
1.1 da of 18,17-tetramethyl-2LH,23H-porphine-2,18-dipropionic acid chloride was obtained.

Example 1 7.12-jethynyl-8,8,13,17-tetramethyl-2,18-bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-21H.

Synthesis of 28H-porphine 7. 12-jethynyl-a, s, ia, 17-tetramethyl-21H,23H-porphine-2,18-
1.1 g of dipropionic acid chloride was added to 6 methylene chloride.
(In addition to lyt, 5 ml of 2-dimethylaminoethanol was added under reflux and refluxed for 45 minutes. After further adding 5 ml of 2-dimethylaminoethanol and refluxing for 45 minutes, the G medium was distilled off under reduced pressure. Add 100rt of chloroform to the residue, wash with 100ml of water, and concentrate the chloroform layer to dryness under reduced pressure.The concentrated and dried product is filled with alumina (activity y) using chloroform as a solvent. The product was purified by column chromatography to give a dark brown 7,12-jethinyl-3,8,13,17-tetramethyl-2,1 with a molecular weight of 850 ~
8-bis(2'-(2-dimethylaminoethyloxy)
Crystals of (carbonylethyl)-2LH,23H-porphine were obtained.

Melting point 187-191″C Visible absorption maximum (in chloroform) 407.506,541,577.630 (4m) Infrared absorption spectrum (K]3r) 8305.2960,2940,2900,2850°2810.2760.1715 (α) Nuclear magnetic resonance spectrum (in deuterated chloroform) δ; 9.70.9.56.
9.49 (s, 2H, LH, LH) 8.10-7.7
2 (m, 2H) 6.24-5.92 (m, 4H) 4.26 (t, 4H) 4.15 (t, 4H) 3.44, 8.88, 8.36, 8.84 ( s, 3HX
4) 3.19 (t, 4H) 2.86 (t, 4H) 2.06 (s, 12H) -4,48(S, 2) I) Example 2 7.12-jetinyl-8,8, 13,17-tetramethyl-2,18-bis(2-(1,3-bis(dimethylamino)-2-propyloxy)carbonylethyl)-
Synthesis of 21J23H-porphine 7,12-jethynyl-3,8,13,17-tetramethyl-2LH,23H-porphine-2,18-
Condensation of 1.1 dipropionic acid chloride and 5 tttl of 1,3-bis(dimethylamino)-2-propanol yields 480 ~ dark brown 7,12-jethynyl-3
,8,13,17-tetramethyl-2,18-bis(2
-(1,8-bis(dimethylamino)-2-propyloxy)carbonylethyl) -21H,28H-porphine was obtained.

Melting point 181-190"c Visible absorption maximum (in chloroform) 407.5.505.5.541.576.680.5
(nm) Infrared absorption spectrum (KBr) 8805.2960, 2930, 2900, 2850° 2810.2760, 1780 (α) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ: 9.79.9.76,
9.62.9.56 (s, IHx4) 8.14-7
．． 76 (m, 2H) 6.24-5.92 (m, 4H) 5.13 (t, 2H) 4.82 (t, 41() 8.48.3.44.3.39 (s, 3H) ,8H,
6H) 8.21 (t, 4H) 2.21 (d, 8l-1) 2.04 (S, 24H) -4,32(s, 2H) Example 3 7.12-jethynyl-8,8, 13,17-tetramethyl-2,18-bis(2-(6-dimethylamino-1
-hexyloxy)carbonylethyl)-21H,2[
(Perform the same operation as in Synthesis Example 1 of -porphine) to obtain 7,12-jethynyl-3,8,18,17-titramethyl-21H123H
-Porphine-2,18-dipropionic acid chloride 1
．． 1 g to 5 m of 6-dimethylamino-1-hexanol
condensation with 450q of blackish brown 7゜12-jethynyl-8,8,13,17-tetramethyl-2,18-
Bis(2-(6-dimethylamino-1-hexyloxy)carbonylethyl) -2LH.

Obtain crystals of 23H-porphine.

Melting point 160-165°C Visible absorption maximum (in chloroform) 407.5, 505.5, 541, 576.630.5
(nm) Infrared absorption spectrum (KBr) 8300.2920, 2850, 2800, 2750° 1785 (α) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.7
．． 9.6.9.52 (s, 2H, IH, LH) 8.2
-7.7 (broad 2H)6.28-5.9
(m, 4H) 4・27 (t, 4H) 4.02 (t, 4H) 3.42, 3.38 (s, 6H, 6H) 3.16
(t, 4H) 2.02 (S, 12H) 2 - 1.8 (m, 4H) 1.5 -1.2 (m, 4H) 1.2 -0.
9 (m, 16H)-4,6(broad, 2
H) Example 4 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-(N-(2-dimethylaminoethyl)carbamoyl)ethyl)-2LH,2[( −
Synthesis of porphine The same operation as in Example 1 was performed to obtain 7,12-jethinyl-3,8,13,17-tetramethyl-21H923H.
-Porphine-2,18-dipropionic acid chloride 1
．． 1F to 2-dimethylaminoethylamine 5 yttl
and condensation to give 740 ~ dark brown 7.12-jethynyl-8,8,13,17-titramethyl-2゜18-bis(2-(N-(2-dimethylaminoethyl)carbamoyl)ethyl)-2LH, Obtain crystals of 23H-porphine.

Melting point 300"C or more Visible absorption maximum (in chloroform) 406.5, 506, 541, 576.630 (nm)
Infrared absorption spectrum (KBr) 8290.2925, 2850, 2805, 2750° Nuclear magnetic resonance spectrum (in deuterium chloroform) δ: 9.4
4.9.89.9J4.9.19 (s, 1Hx4)
8.06-7.62 (m, 2H) 6.8-6.6 (m, 2H) 6.21-5.88 (m, 4)I) 4.02
(broad, 4H) 3.28.3.26.3
．． 24.3.15 (S, 8HX4) 3.04-2
．． 76 (m, 4HX2) 1.76.1.73 (t, 2) IX 2 ) 157
, 1.58 (s, 6Hx2) - 5,05 (S, 2
f-I) Example 5 7.12-jethynyl-8,8,13,17-tetramethyl-2,18-bis(2-(N-C8-dimethylaminopropyl)carbamoyl)ethyl)-2LH,23H
- Synthesis of porphine The same procedure as in Example 1 was carried out to obtain 7,12-jethinyl-3,8,18,17-tetramethyl-21H928H.
-Porphine-2,18-dipropionic acid chloride 1
．． 1F and 5 ml of 3-dimethylaminopropylamine were condensed to give 650 ~ dark brown 7,12-diethenyl-3,8,13,17-titramethyl-2.18-bis(2-(N-(3-dimethyl Crystals of (aminopropyl)carbamoyl)ethyl) -12L H,23H-porphine were obtained.

Melting point 300°C or higher Visible absorption maximum (in chloroform) 407.505.5,541,576.630<nm)
Infrared absorption spectrum (KBr) 3300.3075, 2920, 2850, 2800° 2750.1640 (mouth) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.5
3.9.39.9.28 (s, 2H, IH, LH)
8.09-7.65 (m, 2H) 7.55-7.85 (m, 2H) 6.23-5.88 (m, 4H) 4.05 (t, 4H) 8.33.3. 28.3.27.3.12 (S, 3
HX4 ) 2.92 (t, 4H) 2.85 (t, 4H) 1.66-1.5 (t, 4H) 1.6 B, 1.59 (s, 6HX 2 )1.
11 (q, 4H) -4,88 (s, 2H) Reference Example 2 3,8.1ull, 17-titramethyl-21H,2
3I(-Synthesis of porphine-2,18-dipropionic acid chloride 3, 8.18.17-tetramethyl-2LH,23H-
Porphyne-2,18-dipropionic acid 1f was mixed with 35ml of methylene chloride? Oxalyl chloride was suspended in 2.5 Mt lI! under reflux. The reaction is completed by adding dropwise and continuing to reflux for 15 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and 3, 8. IL 17-tetramethyl-21H,
1.1y of 23H-porphine-2,18-dipropionic acid chloride was obtained.

Example 6 a, s, ia, 17-tetramethyl-2,18-
Synthesis of bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-21H,2LH-porphine 3, 8.18.17-tetramethyl-21H,28H-
Porphyne-2,18-dipropionic acid chloride 1.
1 g was added to 60 tttt of methylene chloride, and 5 stl of 2-dimethylaminoethanol was added to the mixture under reflux.
After refluxing for 5 minutes, 2-dimethylaminoethanol 5
After adding tnl and refluxing for an additional 45 minutes, the solvent was distilled off under reduced pressure, the residue was dissolved in 10011 t of chloroform, washed with a large amount of water, and the chloroform layer was concentrated to dryness under reduced pressure to obtain a residue. was purified by column chromatography using chloroform as a solvent and 100 fI of alumina (activity V) as a packing material to obtain 330q of dark brown crystals of 3,8°13.17-tetramethyl-2,18-
330 da of bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-2LH,23)I-porphine was obtained.

Melting point 159-161"C Visible absorption maximum (in chloroform) 399, 496.5.529.5.566, 591.5
゜6L9 (nm) Infrared absorption spectrum (KBr) 3800.2925, 2845, 2805, 2755゜Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.7
7.9.68.9.67 (s, IH, LH, 2) I
) 8.76.8.75 (s, 1HX2) 4.25 (t, 4H) 4.12 (t, 4H) 3.56.3.48.3.44.3.89 (s, 3H
X4) 3.10 (t, 4H) 2.82 (t, 4H) 2.04 (s, 6H) -4,81 (S, 2I-I) Reference Example 3 7.12-diethyl-a, s, Synthesis of ta, 17-tetramethyl-2LH,23H-porphine-2,18-dipropionic acid chloride 7. 12-diethyl-3,8,13,17-tetramethyl-21H,21H-porphine-2,18- 1 g of dipropionic acid was suspended in 35 ml of methylene chloride, and 2.5 ml of oxalyl chloride was added dropwise under reflux.
The reaction is completed after refluxing for a minute. The solvent of the reaction solution was distilled off under reduced pressure, and 1.1F of 7,12-diethyl-8 was added to the residue.
,8,18,17-tetramethyl-21H,2:9H-
Porphine-2,18-dipropionic acid chloride was obtained.

Example 7 7. Synthesis of 12-diethyl-3,8,13,17-tetramethyl-2,18-bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-21H,28H-porphine 7,12 -diethyl-s, s, ta, 17-titramethyl-211-1.23H-porphine-2,18
- Dipropionic acid chloride 1.11 to methylene chloride 6
Add 0 ml and reflux, add 5 tttl of 2-dimethylaminoethanol and reflux for 45 minutes,
Add another 5 at of 2-dimethylaminoethanol to 4
After refluxing for 5 minutes, the medium is distilled off under reduced pressure, and the residue is dissolved in 100 ml of chloroform and washed with water. The chloroform layer was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography using 100f alumina (activity V) as a packing material and chloroform as a medium to obtain 7,12-diethyl-3 of 930~. ,8,18,
17-tetramethyl-2,18-bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-21H
, 23H-porphine blackish brown crystals were obtained.

Melting point 168-172°C Visible absorption maximum (in chloroform) 399.5,498,582,567.598.5°6
20.5 (71m) Infrared absorption spectrum (KBr) 3305.2955, 293C1, 2855, 2810
゜2710.1735 (α) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.9
2, 9.87, 9.83, 9.81 (S, IHX4) 4
．． 85.4.32 (t, 2HX2) 4.13
(t, 4H) 3.94.8.91 ((1,2f(X2)3.56
．． 3.50.3.44'(s, 3H,6H,3H)3
．． 25 (t, 4H) 2.88 (t, 4H) 2.02 (S, 6I() 1.78, 1.77 (t,, 2Hx2) - 3,92 (s
, 2H) Example 8 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2'-5!-trimethylammonioethyloxy)carbonylethyl H,28H-porphiindiaio 7,12- obtained in Synthesis Example 1 of Dido
Jetinil-8. 8, 13.

I7-Tetramethyl-2,18-bis(2-(2-dimethylaminoethyloxy)carbonylethyl)-2LH
, 23H-porphine lOOq to methylene chloride LOmt
7,12-jetinyl-3. of 1 2 6 #lf is obtained by adding methyl iodide l tttl f and precipitating crystals. 8, 13, 17-tetramethyl-2
, 18-bis(2-(2-trimethylammonioethyloxy)carbonylethyl)-2LH,28H-porphine diiodide was obtained as dark brown crystals.

Visible absorption maximum (in water) 676, 512, 548, 576, 5.6a0.5 (g
m) Infrared absorption spectrum (KBr) 3800, 2900, 1725 (reserve) Nuclear magnetic resonance spectrum (in DMSO-d6) δ; 9.74, 9.66 (
s, 2HX2) 8, 4 -7.8 (m, 2H) 6, 4 -6.0 (m, 4H) 4, 5 -4.0 (broad, 4HX2) 3,
4 8 (s, 8Hx4) 3, 2 6
(broad, 4Hx2) 2, 79
(s, 18H) -5.0 8 (broad, 2H) Example 9 7,12-jetinyl-3. 8,13. 17-tetramethyl-2,18-bis(2-(1,8-bis(trimedelammonio)-2-propyloxy)carbonylethyl)-211(, 23H-Porphine tetraiodide Synthesis Example 2 The obtained 7,12-dietheni"ru a, s,
t. q.

17-tetramethyl-2,18-bis(2-(1.3-
Bis-(dimethylamino)-2-propyloxy(2-)carbonylethyl)-21H,28H-porphine 100
Wl was dissolved in methylene chloride LOml, and methyl iodide l
tttt was added and the precipitated crystals were put into the furnace and 100 Da of 7,12-jetinyl-8. 8, 13. 17-tetramethyl-2,18-bis(2-(,I,-8
, (bis-trimethylammonio)-2-propyloxy)carbonylethyl)-2LH,23H-porphine tetraiodide was obtained as dark brown crystals.

Visible absorption maximum (underwater) 398,509,543.5,578.5,628.5
(nm) Infrared absorption spectrum (KBr) 8300.2995, 2910, 2850°1740 (
α) Nuclear magnetic resonance spectrum (in DMSO-d6) δ; l
O, 20-9, 96 (s, IHx4) 8.52-8
．． 02 (m, 2H) 6.44-6.06 (m, 4H) 5.88-5.58 (broad, 2H) 4.68
-4.28 (broad, 4H) 3.96-8
．． 4 (m, 4H, 4H, 4H) 8.64-3.5
6 (8, 8HX4) 3.08 (s, 86H
) -4,26(broad, 2H) Example i.

7.12-jethinyl-8,8,13,17-tetramethyl-2,18-bis(2-(N-C2-trimethylammonioethyl]carbamoyl)ethyl]-2LH,2
3f(-7,12-jethynyl-3,8,1B obtained in Synthesis Example 4 of Borufindiaiodide.

17-tetramethyl-2,18-bis(2-(N-(2
-dimethylaminoethyl)carbamoyl)ethyl)-2
1H,23H-porphine was heated and dissolved in 2011 t of methylene chloride, then returned to room temperature and methyl iodide was added. ,8゜13
．． 17-tetramethyl-2,18-bis(2-(N-(
Dark brown crystals of 2-)limethylammonioethyl)carbamoyl)ethyl)-2LH,23H-borfindiaiodide were obtained.

Visible absorption maximum (in water) 377.5,510,548,575.5,630 (n
m) Infrared absorption spectrum (KBr) [00,8230,2995,2900,2845°1
655 (ffi) Nuclear magnetic resonance spectrum (in DMSO-d6) δ: 10.
2-10.05 (s, IHX4) 8.6-8.0 (
m, 2H) 6.6-6.0 (m, 4H) 4.87 (t, 4H) 8.8 -3.6 (m, 8H) 8.28
(broad, 8Hx4) 3.14
(t, 4H) 2.54 (s, 18H) Example 11 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-(N-(8-)limethyl ammoniopropyl)carbamoyl)ethylcou 2LH,
Synthesis of 23H-borufindiaiodide 7,12-jethinyl-3,8,13゜17-tetramethyl-2,18-bisC2-(N-(3
-dimethylaminopropyl]carbamoyl)ethyl)-
211 (,23H-Porphine OOIIg was dissolved in methylene chloride 1O1, 1 tgl of methyl iodide was added, the precipitated crystals were collected, and 126ffi of 7°12
-jetinyl-3,8,13,17-tetramethyl-2
,18-bis(2-(N-(3-)limethylammoniopropyl)carbamoyl)ethylcou21H,21H-
Black-brown crystals of porphindia iodide were obtained.

Visible absorption maximum (in water) 880.5, 510, 546, 577.681 Cnm)
Infrared absorption spectrum (KBr) 3800,:1I250,2900,2850°'16
40(1:'III) Nuclear magnetic resonance spectrum (in DMSO-ds) δ; 9.
94.9.86.9.78(S, 11-I, 11(
, 2H) 8.5-8.06 (m, 2H) 8.02-7.86 (m, 2H) 6.4-6.09 (m, 4H) 4J (broad, 4H) 3.54
(broad, L 2H) 3.1-2.8 (b
road, 8H) 2.62 (broad,
4H)L8 (broad, 4H)4
, 9 (broad I 2 H) Example 12 7.12-jethynyl-8,8,11,17-tetramethyl-2,18-bis(2-(2-hydroxyethyloxy)carbonylethyl) -2LH,23H -Synthesis of porphine The same operation as in Example 1 was carried out to obtain 7,12-jethinyl-8,8,13,17-titramethyl-21H.

1.1 g of 23H-porphine-2,18-dipropionic acid chloride was condensed with 5 wtl of 1,2-ethanediol to produce 450 Ml of dark brown 7,12-jethynyl-1,8,13,17-tetramethyl. Crystals of -2,18-bis(2-(2-hydroxyethyloxy)carbonylethyl)-21H,23H-porphine were obtained.

Visible absorption spectrum (in chloroform) 406.5,
505.5, 541.5, 575.5, 6: dO<nm
) Infrared absorption spectrum (KBr) 8B90, 8300, 2900, 2850° 1735 (
cIN ) Nuclear magnetic resonance spectrum (in CFaCO2D) δ; 8.3
6-8.0 (m, 2H) 6.61-6.22 (
m, 4H) 4.8 -4.5 (m, l2H) 8.81. −
3.79, 8.75 (s, 3H, 6H, 8H) 3.27
(t, 41() Example 13 7.12-jethynyl-3,8,18,17-tetramethyl-2,18-bis(2-(benzyloxy)car'
Synthesis of 7,12-jethynyl-8,8,13,17-titramethyl-21f(bonylethyl)-2LH,2'8H-porphine The same operation as in Example 1 was carried out.

By condensing 1.1 g of 23H-porphine-2,18-dipropionic acid chloride with 51 It of benzyl alcohol, a dark brown 7,12-jethynyl-8 of 69019 was obtained.
8,18,17-tetramethyl-2,18-bis(2-
(benzyloxy)carbonylethyl)-21H,23
Crystals of H-porphine were obtained.

Melting point 185-189°C Visible absorption maximum (in chloroform) 408.505.5,541,576.630 (flm
) Infrared absorption spectrum (KBr) 8300.3080, 8050, 8020, 2400°2850.1735 (reserve) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 9.6
0.9.56.9.52.9.36(s, 1f(x4
)8.09-7.70 (m, 2H) 6.98 (S, 10H) 6.22-5.90 (m, 4H) 4.99 (S, 41() 4.16 (t, 4H) 3J2, 3.24 (S, 3Hx3,8H) 3.15
(t, 4EI) -4,66(s, 2H) Example 14 7.12-jethynyl-3,8,13,17-tetramethyl-2,18-bis(2-(P-nitrobenzyloxy)carbonyl ethyl) -21H,23f(-Synthesis of porphine The same procedure as in Example 1 was performed to obtain 7,12-jethynyl-3,8,13,17-tetramethyl-21H923H.
,-Porphin-2,18-dipropionic acid chloride 1. Condensation of LI and P-nitrobenzyl alcohol 5Ht gives 720cm of blackish brown 7,12-jethinyl-8.
,8,13,17-titramethyl-2゜18-bis(2
-(P-nitrobenzyloxy)carbonylethyl)-
Crystals of 21H,28H-porphine were obtained.

Melting point 191-195°C Visible absorption maximum (in chloroform) 408, 506.541.576.680 (nm) Infrared absorption spectrum (KBr) 3300.3070, 2900, 2850, 1740° 1520.1345 (cIN) Nucleus Magnetic resonance spectrum (0DO1a-OFaCO2D
) δ; l O,74,10,56,10,49(s,
LH, LH, 2H) 8.19-7.9 (m, 2
H) 7.92.7.20 (d, 4Hx2) 6.40-
6.10 (m, 4H) 4.96 (s, 4H) 3.65.3.63.8.56,8.54 (s, 3Hx
4) 2.10 (t, 4H) Example 15 7,12-jethynyl-8,8,18,17-tetramethyl-2,18-bis(2-(2-mercaptoethylthio)carbonylethyl)-2LH , 23H-porphyi The same procedure as in Example 1 was carried out to produce 7,12-jethynyl-8,8,13,17-titramethyl-21f (.

1.1 g of 23H-porphine-2,18-dipropionic acid chloride was condensed with 5 ml of 1,2-ethanedithiol to produce 320 My dark brown 7,12-jethynyl-3,8,18,17-tetramethyl. -2,18-bis(2-(2-mercaptoethylthio)carbonylethyl)-21H,23H-porphine was obtained.

Visible absorption maximum (in chloroform) 407.5, 507, 540.5, 576.5, 680
(nm) Infrared absorption spectrum (KBr) 8300.2900,2840,2540°1690(
Image] Nuclear magnetic resonance spectrum (in 0FBOO2D) δ; 10
．． 52.10.45.10.42. IOJ 1(S,
IHX4)7.9 -7.4 (m, 2H)6
．． 1 -5.7 (m, 4H)4.1
(broad, 4H) 8.81 (br
oad, 8H) 3.28 (s, 12H) 2.8 (broad, 4H) Example 16 7.12-jethynyl-8,8,13,17-tetramethyl-2,18-bis(2-(benzylthio) 9carbonylethyl)-2LH,28I(-Synthesis of porphine The same procedure as in Example 1 was performed to obtain 7,12-jethynyl-8,8,18,17-tetramethyl-21H221H.
-Porphin-2,18-dipropionic acid chloride °
1.1 g of thiobenzyl alcohol and 5 tttl of thiobenzyl alcohol to give 510 WIg of dark brown 7,12-jethynyl-3,8,13,17-titramethyl-2.18
-bis(2-(benzylthio)carbonylethyl)-2
Obtain crystals of LH,2LH-porphine.

Melting point 116-122°C Infrared absorption spectrum (KBr) 8800.8050, 8015, 2990, 2950° 2900.2850, 2800.1680 (G) Nuclear magnetic resonance spectrum (in deuterium chloroform) δ; 10.
64.10.46.10.42.10.84 (s, I
HX4) 8.3 -7.7 (m, 2H) 7.14 (S, 10H) 6.4 -6.1 (m, 4H) 4.4 -4.
2 (broad, 4H) 4.08 (s
, 4H) 3.56.3.46 (S, 6H, 6H) 3.42
(t, 4H) -IJ--1,8 (broad, 2H) Reference Example 4 Cancer Cell Affinity 10 x 10 MKSA cells derived from kidney fibrosarcoma from a 3-week-old Ba1b/c mouse were transplanted into the back of a 1G mouse. , 2~
After 3 weeks, 20% of the porphyrin derivative obtained according to the present invention was added.
Administer into the tail vein at a rate of 111 f/kg (body weight).

After 24 hours, each organ and cancer cells are removed and the fluorescence derived from the porphyrin derivatives emitted from them is detected using a laser diagnostic device [Katsuo Kanazawa et al., Journal of the Laser Medical Society, Vol. 5, 6:11-
68 (1984). The results are summarized in Table 1, expressed as the ratio of the fluorescence intensity at the normal site to the fluorescence intensity at the tumor site, and the fluorescence intensity at the tumor site. In the table, [■] and (X) are respectively Example 8
and IO' compound, Hp is hematoporphyrin, HpD is the above-mentioned Porphyrin Localiz
ation and Treatment of Tum
It is a porphyrin derivative obtained according to the description in J. Ors, pp. 75-78 (1984).

Table 1 Reference Example 5 Treatment effect MKSA cells 1 on the back of a 3-week old Ba1b/c mouse
x107 pieces were transferred, and after 2 to 3 weeks, when the diameter of the cutout grew to about ltM, 7,12-jetinyl-3,8,18,17-tetramethyl-2, obtained in Example 8, 1
8-bis(2-(2-)-limethylammonioethyloxy)carbonylethyl)-21H,23H-porphine diiodide per 1 kq of mouse body weight 1) 20”f
was administered via the tail vein at a rate of 24 hours after administration - The hair above the tumor was shaved to expose the skin and irradiated with excimer dye laser (wavelength 625 nm), and the tumor disappeared 3 days later.

Effects of the Invention The compounds of the present invention are pure porphyrin derivatives synthesized using deutroporphyrin [, mesoporphyrin IX, and protoporphyrin [2] according to the Fisher nomenclature.

In addition, each of these porphyrin derivatives has the ability to accumulate in cancer cells, emitting fluorescence when irradiated with light, and when irradiated with light in the presence of oxygen, generates 702, and this '02 causes cancer cells to emit fluorescence. Since it has a killing effect, it is useful as a cancer diagnostic and therapeutic agent.

Patent applicant: Hamari Pharmaceutical Co., Ltd. Representative Takupa Takeuchi.

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the above general formula, R_1 is a hydrogen atom, lower alkyl group, or vinyl group; R_2 is ▲ There are ▲ mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas , tables, etc. ▼, ▲ mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A, B, C
are each a lower alkyl group, X is a halogen atom, m is 1
~23, n represents an integer of 1 to 4, or represents a benzyloxy group, a benzylthio group, or a benzylamino group, which may have a substituent)]. (2) General formula▲ Numerical formulas, chemical formulas, tables, etc. are available▼ [In the above general formula, R_1 is a hydrogen atom, a lower alkyl group, or a vinyl group; X represents a halogen atom. ) is the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, HO(CH_2CH_2O)_nH or HS(CH_
2CH_2S)_nH (wherein A and B are each a lower alkyl group, m is an integer of 1 to 23, and n is an integer of 1 to 4)]
A general formula characterized by condensation with a compound represented by or a salt thereof or benzyl alcohol, thiobenzyl alcohol, or benzyl amine which may have a substituent ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is the same as above; R_3 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc. ▼、O(CH_2CH
_2O)_nH or S(CH_2CH_2S)_nH
(A and B are lower alkyl groups, m is 1-23, n
represents an integer of 1 to 4), or a benzyloxy group,
a benzylthio group or a benzylamino group, which may have a substituent. (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the above general formula, R_1 has the same meaning as above; R_4 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, m is an integer from 1 to 23, and A and B each represent a lower alkyl group)] A general formula characterized by reacting a derivative with a lower alkyl halide ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the above general formula, R_1 has the same meaning as above; R_5 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A, B, C
are each a lower alkyl group, X is a halogen atom, m is 1
A method for producing a porphyrin derivative represented by: