JPH0311080A - Novel porphyrin derivative and its salt - Google Patents

Abstract

NEW MATERIAL:A compound of formula I {R<1> is H, (di)lower alkylamino or (substituted)nitrogen-contg. heterocyclic group binding via N in ring; R<2> is (di)lower alkylaminomethyl or -CH2R<3> [R<3> is (substituted)nitrogen-contg. heterocyclic group binding via N in ring] when R<1> is H; when R<1> is (di)lower alkylamino, R<2> is (hydroxy)methyl, lower alkoxycarbonyl, halogenomethyl, etc.}. EXAMPLE:3,8,13,17-tetramethyl-7,12-bis[2-(piperidine-1-yl)ethyl]porphy rin-2,18- dipropionic dimethyl ester hydrochloride. USE:Carcinostatics. PREPARATION:A compound of formula II is reacted with a second compound of formula R<1a>H (R<1a> is R<1>) in the presence of, where appropriate, an inert solvent such as chloroform and/or a base.

Description

[I
] "In the formula, R1 is a hydrogen atom, a hydrogen atom, a lower alkylamino group,
A di-lower alkylamino group or an optionally substituted nitrogen-containing heterocyclic group bonded via a nitrogen atom in the ring: R
2 is a lower alkylaminomethyl group, a di-lower alkylaminomethyl group, or a formula -CHR3 (wherein, R3 is an optionally substituted group bonded via a nitrogen atom in the ring) when R1 is a hydrogen atom. Indicates a nitrogen-containing heterocyclic group.

): When R1 is a lower alkylamino group, di-lower alkylamino group, or an optionally substituted nitrogen-containing heterocyclic group bonded via a nitrogen atom in the ring, R2 is , a methyl group, a hydroxymethyl group, a carboxyl group, a lower alkoxycarbonyl group, a halogenomethyl group, or a carbamoyloxymethyl group which may be substituted with a lower alkyl or aryl group.

” and its salts.

[Prior Art] Conventionally, as a compound in which a substituent group of a porphyrin derivative is bonded via a nitrogen atom, a JP-A-63-C alkyl group is used; X represents 1 to 4 halogen atoms. ), a pyridinium halide group which may have a substituent, or a quinolinium halide group which may have a substituent. A compound to which a quaternary ammonium salt type group represented by " is bonded is described.

On the other hand, as a substituent, the formula -1\--R1 and /'\/
Porphyrin derivatives and salts thereof to which a group represented by R2 (R1 and R2 have the same meanings as described above) are bonded are not known.

[Problems to be Solved by the Invention] Porphyrin derivatives used in the treatment of cancer mainly include hematoporphyrin derivatives (HpD), which in normal tissues include the liver, kidneys, spleen, and lymph nodes. , has an affinity for bone marrow, skin, etc. but,
Since HpD has the property of remaining in cancerous tissues for a long time, it is gradually excreted from normal tissues over time, resulting in a high concentration in cancerous tissues.

Furthermore, since HpD is a photosensitizing substance, it is well known that if a cancer patient administered with HpD is exposed to sunlight without sufficient exposure for one hour, solar dermatitis will occur.

Therefore, in therapy using HpD, cancer patients are forced to deprive themselves of natural light for a long period of time, for example, 2 to 4 weeks, after drug administration.

In addition, therapy using HpD is limited to organs where optical fibers can be used remotely (e.g., lungs, stomach, etc.);
Furthermore, there is a limit to the ability of laser light to penetrate tissue, so there are problems such as only superficial tumors can be treated.

In order to solve this problem, it has been desired to develop a compound that does not have a cell-killing ability based on photosensitization but instead exhibits a cell-killing ability directly against cancer cells.

The purpose of the present invention is not cell killing ability based on photosensitization effect,
The object of the present invention is to provide porphyrin derivatives and salts thereof that exhibit cell-killing ability directly against cancer cells.

[Means for Solving the Problems] Under these circumstances, the present inventors conducted extensive research and found that the above-mentioned novel porphyrin derivative of general formula [I] and its salt solve the above problems. , we have completed the present invention.

The present invention will be explained in detail below.

In this specification, unless otherwise specified, a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; a lower alkyl group refers to, for example, methyl, ethyl, n-propyl, isopropyl, n- butyl,
C alkyl group such as isobutyl, sec-butyl, tert-butyl, pentyl or hexyl: lower alkoxy group 1-6 means lower alkyl-〇- group: lower alkylamine group means lower alkyl-NH- group A di-lower tolyl group or a naphthyl group; a halogenomethyl group refers to a chloromethyl or bromomethyl group; a nitrogen-containing heterocyclic group refers to, for example, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a tetrazolyl group, or a triazolyl group. Each refers to a 5- or 6-membered nitrogen-containing heterocyclic group having a nitrogen atom in the ring that can be bonded without becoming tetravalent.

Examples of the substituent of the optionally substituted nitrogen-containing heterocyclic group in R1 and R3 include a lower alkyl group, a halogen atom, and an oxo group.

- The salt of the porphyrin derivative of formula [I] is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include salts with basic groups or acidic groups.

Specifically, as a salt in a basic group, for example,
Examples of salts with acidic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, and salts with alkali metals such as sodium or potassium.

Furthermore, when isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist in the porphyrin derivative of formula [I] and its salt, the present invention includes all such isomers. However, it also includes all crystalline forms, solvates and hydrates.

Next, the method for producing the porphyrin derivative of general formula [I] and its salt of the present invention will be explained.

- The porphyrin derivative of formula [I] or a salt thereof can be obtained by combining known methods, and can be produced, for example, according to the production route shown below.

"In the formula, Rla is the same lower alkylamino as R1,
Di-lower alkylamino or an optionally substituted nitrogen-containing heterocyclic group bonded via the nitrogen atom in the ring: R1
b is a lower alkyl group or a triazolyl or tetrazolyl group optionally substituted with a halogen atom: R
4 represents a lower alkyl group; 2 R5 represents a hydrogen atom, a lower alkyl group or an aryl group; X represents a halogen atom; ” As the salt of the compound of general formula [ial, [from], [Icl, [Id], [e], [If] or [Icx], - the same as explained for the salt of the compound of formula [I] Examples include salt.

Next, the method for producing the compound of formula [I] or its salt will be explained in more detail according to the above-mentioned production route.

(1) - Reaction with the compound of formula [l11a] (-formula [l11a]
Process for producing compounds of [Eng a], [Ibl, [If] or [ICl] or salts thereof) - Formulas [II], [V], [VI] Matc [VI]
(7) By reacting the compound with a compound of formula [Ial, [Ibl, [If] or [Ig]] in the presence or absence of a solvent inert to the reaction, - a compound of formula [Ial, [Ibl, [If] or [Ig] or You can get those salts.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but examples include halogenated hydrocarbons such as chloroform, methylene chloride and dichloroethane; ethers such as tetrahydrofuran and dioxane. ; Aromatic hydrocarbons such as benzene, toluene and xylene Nitriles such as niacetonitrile and propionitrile; Amides such as N,N-dimethylformamide and N,N-dimethylacetamide; Phosphoramides such as hexamethylphosphoramide and sulfoxides such as dimethyl sulfoxide, and these solvents may be used alone or in combination of two or more.

Moreover, this reaction can also be performed in the presence of ml.

Examples of the base that may be used as necessary in this reaction include non-microbases such as alkali hydrogencarbonate, alkali carbonate, and alkali hydroxide; and organic bases such as triethylamine, tripropylamine, and tributylamine.

The compound of general formula [I[1a] may be used in excess as a base. Moreover, the compound of formula [IIIa] may be used as a salt with sodium or potassium.

The amount of the compound of general formula [l11a] to be used is - formula [II
], [V], [V! ] Mataha [VI] (7) At least 2 times the mole of each compound, preferably 2.0
~10 times the molar amount.

The reaction temperature and reaction time are not particularly limited, but from 20 to
What is necessary is just to carry out at 100 degreeC for 30 minutes - 48 hours.

The general formula [Ial or [Ibl] thus obtained
The compounds or their salts may be used as they are in the reaction without isolation.

(2) Reduction with a reducing agent The compound of general formula [A] or [X] or a salt thereof is treated with a reducing agent such as lithium aluminum hydride or sodium cyanoborohydride in the presence of a solvent inert to the reaction. By reacting, a compound of formula [Ibl or [ICl3] or a salt thereof can be obtained.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but examples include ethers such as tetrahydrofuran and dioxane; and phosphoramides such as hexamethylphosphoramide. Moreover, these solvents may be used alone or in combination of two or more.

The amount of the reducing agent to be used is - equivalent mole or more relative to the compound of formula [Ial or [X] or a salt thereof, respectively;
Preferably, it is 2 to 4 times the molar amount.

The reaction temperature and reaction time are not particularly limited, but -10
What is necessary is just to carry out at -100 degreeC for 1 minute - 2 hours.

(3) Halogenation By reacting a compound of the general formula [Ibl or a salt thereof with a halogenating agent such as carbon tetrabromide-triphenylphosphine or thionyl chloride in the presence of a solvent inert to the reaction, - A compound of [Ie] or a salt thereof can be obtained.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but examples include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; acetonitrile. and nitriles such as propionitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; phosphates such as triethyl phosphate; and pyridine; You may use a mixture of more than one species.

The amount of the halogenating agent to be used is at least 2 times the mole, preferably 2.0 times the amount of the compound of Ibl or its salt.
~6.0 times the mole.

The reaction temperature and reaction time are not particularly limited, but 0 to 6
What is necessary is just to carry out at 0 degreeC for 5 minutes - 10 hours.

(4) Reaction with isocyanates By reacting the compound of the general formula [Ibl or its salt with isocyanates in the presence or absence of a solvent inert to the reaction, the compound of the general formula [Ibl] or You can get that salt.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but examples include halogenated hydrocarbons such as methylene chloride and chloroform; aromatic solvents such as benzene, toluene and xylene. Hydrocarbons: Examples include ethers such as tetrahydrofuran and dioxane; pyridine; and amides such as N,N-dimethylformamide; and these solvents may be used alone or in combination of two or more.

Examples of the isocyanates include C1-6 alkyl isocyanates such as methyl isocyanate or ethyl isocyanate; aryl isocyanates such as phenyl isocyanate; and isocyanates such as chlorosulfonyl isocyanate or sodium cyanate.

Also, sodium cyanate is preferably used in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid or an 11EII such as trifluoroacetic acid or trichloroacetic acid.

The amount of the inorganic acid or organic acid used is at least equimolar to sodium cyanate.

The amount of isocyanate used is at least twice the molar amount of the compound of Ibl or its salt.

The reaction temperature and reaction time are not particularly limited, but 10-
What is necessary is just to carry out at 140 degreeC for 10 minutes - 48 hours.

(5) Hydrolysis By subjecting the compound of general formula [Ia] or its salt to conventional hydrolysis using an acid or base,
Id] or a salt thereof.

(6) - Reaction of -Fukudai [111b] with the compound (-Fukudai [111b]
Ia] or [Method for producing a compound of ICl3 or a salt thereof) A compound of general formula [IV] or a compound of formula [■] in the presence of diethyl azodicarpoxylate, triphenylphosphine and a solvent inert to the reaction, -Cost of clothes [I[b
By reacting with the compound of -fukudai [Ia]
Alternatively, a compound of [Iq] or a salt thereof can be obtained.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but specific examples include the same solvents as mentioned in (1) above.

The usage of diethyl azodicarboxylate, triphenylphosphine and the compound of general formula [I[1b] is -
The mole amount is at least twice that of the compound of formula [IV] or the compound of formula [■], respectively.

The reaction temperature and reaction time are not particularly limited, but 0 to 6
What is necessary is just to carry out at 0 degreeC for 1 to 24 hours.

(7) Catalytic Reduction The compound of general formula [IX] or its salt is subjected to conventional catalytic reduction, for example, as described in Biochemical Journal [Bioc
hem, Jco, Vol. 45, pp. 163-170 (194
By applying the method described in 1999) or a method similar thereto, a compound of -Fukudai [IQ] or a salt thereof can be obtained.

General formulas [II], [IV], in the manufacturing method described above,
[Vl, CVII t'; isomers, geometric isomers, tautomers, etc.), all these isomers may be used, and also all crystal forms, solvates and hydrates may be used. .

The compound of general formula [I] or a salt thereof thus obtained can be isolated and purified according to conventional methods such as extraction, purification, and column chromatography.

Next, the general formulas [n], [IV], [Vl, [VI core] and [Vl[
] Compounds of general formula IX] and [X] or salts thereof; and methods for producing compounds of formula [■] will be explained.

Compounds of general formulas [II] and [IV] can be prepared by methods known per se, for example, by Justus Liebigs Ann.
, der Chem, ), No. 1329-1338
Page (1973) and Journal of the American Chemical Society (J.A.C.S.)
, Vol. 97, pp. 6556-6562 (1975)
It can be manufactured by the method described in or a method similar thereto.

- Compounds of the general formulas [IX], lj and [X] or salts thereof; and compounds of the formula [■] can be prepared by combining known methods. However, for example, it can be manufactured according to the manufacturing route shown below.

(Left blank space below) "In the formula, Rla, R4 and X have the above-mentioned meanings."
] and [X'11] as a salt of the compound -Fukudai [
The same salts as those explained in the salt of the compound of [I] can be mentioned.

Further, examples of the reactive derivatives of the compound of formula [■] include acid halides and active amides (or active amides with imidazole).

Then, - Compounds of [V], [VI] and [VI], Compounds of general formulas [IX] and [X] or salts thereof: and Compounds of formula [■] are manufactured by the above-mentioned production route. It will be explained in detail according to the following.

Reactions such as the reaction with the compound of the general formula [l11a] in the above production route [・, reduction with a reducing agent, halogenation, and catalytic reduction are performed in accordance with the above-mentioned production methods (1), (2), and (3).
This can be carried out in the same manner as described in (7).

The compound of -Fukudai [XI] can also be subjected to a conventional hydroboration reaction (reacting borane and then reacting with alkaline hydrogen peroxide), for example, in the Journal of the American Chemical Society (J. A, C
, S, ) Vol. 97, pp. 6556-6562 (197
A compound of the general formula [rl can be obtained by subjecting the compound to the method described in 2005) or a method analogous thereto.

General formulas [XI] and [Xll1 in the production method described above
] and [store]; compounds of formula [XT] and [store]; and formula [X'l! When isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist in the compounds of l and [■] or their salts, all these isomers can be used, and , all crystalline forms, solvates and hydrates can be used.

General formulas [V], [VI], [V
1] and [Xll]; -Fukudai [IX] and [X] compounds or salts thereof; and formulas [■], [
The compounds Xl[ ], [XN] and [bi] may be used as they are in the subsequent reaction without being isolated.

When the porphyrin derivative of the present invention is used as a medicine, excipients and commonly used pharmaceutical carriers, such as lactose, dextrose, sucrose, sorbitol,
Mannitol, glucose, cyclodextrin, talc, starch, methylcellulose, gelatin, gum arabic, polyethylene glycol, carboxymethylcellulose, hydroxypropylcellulose, aluminum stearate, magnesium stearate, vegetable oil, white petrolatum, distilled water for injection, etc., and diluent, etc. Formulation aids may be mixed as appropriate, and these can be prepared by conventional methods into soft or hard capsules, tablets, powders, syrups, granules,
Fine granules, emulsions, suspensions, emulsions, liquids, powder preparations, planing,
It can be administered orally or parenterally in the form of a laxative, subcutaneously, intramuscularly, intravenously, or a drip injection.

The administration method, dosage, and frequency of administration of the porphyrin derivative of the present invention can be appropriately selected depending on the age, weight, and symptoms of the patient.
．． 01-20my and 4y may be administered in one to several divided doses.

Next, the pharmacological effects of representative compounds of the porphyrin derivatives of the present invention will be described.

(1) Anticancer effect HeLa S-3 cell growth inhibition test 10% beef tallow serum 2 in 96-well microtiter plate
ME containing mH glutamine)l (Minimum es
Appropriately dilute the test compound with a culture medium (sentia medium).

Prepare two dilution series, each with 2 x 104 dilutions using the same culture medium.
HeLa S-3 cells prepared at a density of 0.1 d/d are dispensed into each well. Perform these operations as quickly as possible in the absence of external light. One series is cultured as it is in a carbon dioxide incubator at 37°C for 4 days (untreated group). After culturing the other series at 37°C for 1 day in a carbon dioxide incubator, the plate was incubated at 20°C.
Irradiated with light from a 60W (100V) incandescent light bulb for 5 minutes from the height of
Culture at 7°C (light treatment group).

After each culture, the culture supernatant was removed, fixed with ethanol for 10 minutes, and then washed once with physiological saline.

After staining the fixed cells with Giemsa staining solution, the concentration of each cell growth inhibitory effect (IIc) is determined.

The results are shown in Table-1.

Test compound A, 3.8.13.17-titramethyl-7.12-
Bis[2-(piperidin-1-yl)ethyl]porphyrin-2,18-dipropionic acid dimethyl ester B, 2,18-bis(3-hydroxypropyl)-3,
8,13,17-thitramethyl-7.12-bis[2-
(piperidin-1-yl)ethyl]porphyrin hydrochloride C,2,7-bis[2-(4-ethylpiperazine-1-
yl)ethyl]-13,17-bis(3-hydroxypropyl)-3,8,12,18-tetramethylporphyrin hydrochloride, 2.18-bis(3-hydroxypropyl)-3
, 8,13,17-titramethyl-7.12-bis[2
-(morpholin-1-yl)ethyl]porphyrin hydrochloride E, 2,7-bis[2-(4-ethylpiperazine-1-)
yl)ethyl]-3,8,12,18-tetramethyl-
13,17-bis[3-(N-methylcarbamoyloxy)propyl]porphyrin hydrochloride F, 2.18-bis(3-chloropropyl)-3゜8
, 13.17-titramethyl-7.12-bis[2-(
piperidin-1-yl)ethyl]porphyrin hydrochloride control, 7.12-bis(2-pyridinioethyl)-3,
8,13,17-tetramethyl-2,18-bis(2-
Methoxycarbonylethyl H-porphyrin dibromide (JP-A-63-1452
Compound of Example 1 of 83＠) (Hereafter the margin) Table 1 HeLa S-3 cell growth inhibition test) IIc (#/mf) As is clear from Table 1, the compound of the present invention has a photosensitizing effect. It exhibits strong antitumor activity with almost no cancer.

[Effects of the Invention Accordingly, the compound of the present invention is an extremely useful compound as an antitumor agent.

[Example] Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto. Note that the symbols used in Reference Examples and Examples have the following meanings.

Me: methyl, Et: ethyl, n-pr: n-propyl The mixing ratios of mixed solvents are all volume ratios. Unless otherwise specified, the carrier in column chromatography is silica gel [Kieselgel] manufactured by Merck 60
, Art 7734 (Kteselqe160, Art
, y734)] was used.

Reference Example 1 Luphyrin lithium aluminum hydride 9601n'J is suspended in 200 m of tetrahydrofuran. Meanwhile, 5.009 g of protoporphyrin dimethyl ester is dissolved in 300 ml of tetrahydrofuran. This solution is added dropwise to the previously obtained suspension at 0 to 5°C over a period of 30 minutes. Two saturated aqueous sodium sulfate solutions were added dropwise to this mixture over a period of 5 minutes, and the precipitated insoluble matter was removed. Then, the solvent was distilled off under reduced pressure, and the resulting residue was washed with petroleum ether and dried over phosphorus pentoxide to give dark purple amorphous crystals of 2.18-bis(3-hydroxypropyl). −
3,8,13°17-titramethyl-7.12-divinylporphyrin 4.249 is obtained.

U y (2"g' door m; 402,503,538
,575,629IR (Br) ctn-1: 16
20.1590.1435.1360.1215゜11
70, 1095.1050 Reference Example 2 Irin 2.18-bis(3-hydroxypropyl)-3゜8,
13. Dissolve 17-titramethyl-7.12-divinylporphyrin 4.209 in methylene chloride. To this solution, 7.829 g of carbon tetrabromide and 6.18 g of triphenylphosphine are sequentially added, and the mixture is stirred at room temperature for 20 minutes. After adding 20 d of methanol to the reaction mixture and stirring at the same temperature for 10 minutes, the solvent was distilled off under reduced pressure. Pour the resulting residue into 300 ml of chloroform! After washing with water, drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (developing solvent: chloroform) to obtain dark purple amorphous crystals of 2,18-bis(3-bromopropyl)-3,8 3.839 of 13,17-titramethyl-7,12-divinylporphyrin is obtained.

UV (5E, %gQ) nm: 402,504,538
,575,629IR(KBr) cm”; 160
0.1420.1370.1245.1220°119
5.1100.1060 Reference Example 3 17-tetramethylvorphyline 2.18-bis(3-bromopropyl)-3,8°13
．． 1.307 17-titramethyl-7.12-divinylporphyrin is dissolved in 65 m of tetrahydrofuran. At 0-5°C, add 24% sodium borohydride to this solution.
4 mg and boron trifluoride-diethyl ether 0.8
Add 0m sequentially. The mixture was stirred at the same temperature for 30 minutes, roughly stirred at room temperature for 1 hour, cooled on ice, and then 7.42 ml of 1N aqueous sodium hydroxide solution was added dropwise over 10 minutes. Add 0.89 ml of 30% hydrogen peroxide solution to 1 q of the mixture, and stir at room temperature for 1 hour. The reaction mixture was adjusted to pH 7 with 3N hydrochloric acid.
After adjusting to 0, 250 d of chloroform was added and the organic layer was separated. The separated V1 layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure.

The obtained residue was subjected to column chromatography (developing solvent; chloroform:methanol=100:1-25:
1), dark purple amorphous islands of 2,18-bis(3-bromopropyl)-7,12-bis(2-hydroxyethyl)-3,8,13,17-tetramethylporphyrin 410/ Obtain IIg.

uv (IE; g'Q) nm: 396. a98. s31
, 56a, 526IR (K8r) cm, 160
0.1430.1400.1370.1250°123
0, 1210.1110.1040 Reference Example 4 (1) 2.18-bis(3-bromopropyl)-7
゜12-bis(2-hydroxyethyl)-3,8,13
2.009 ml of 17-tetramethylporphyrin is dissolved in 60 ml of hexamethylphosphoramide. Add 1.809% of sodium cyanoborohydride to this solution and
Stir for 90 minutes at 0°C. Add 80% ethyl acetate to the reaction mixture.
0rn! and 500 ml of water were added sequentially, and the temperature was adjusted to 1 H2°O with 1N hydrochloric acid, and then the organic layer was separated. The separated organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The 1q residue was purified by column chromatography (developing solvent: chloroform:methanol = 100:1 to 40:3) to obtain dark purple crystalline 2,7-bis(2-hydroxyethyl)-3, 8,12,18-tetramethyl-13
, 1.23 g of 17-di-n-propylporphyrin in 1
qru.

(2) Dissolve 1.23 g of the compound obtained in (1) in 10 parts of methylene chloride. Add 2.0% carbon tetrabromide to this solution.
869 and triphenylphosphine 2.269 are added sequentially and stirred at room temperature for 30 minutes. 107 methanol in the reaction mixture! After stirring at the same temperature for 10 minutes, 100 d of chloroform and 20 d of water were added, and the precipitated layer was separated. The separated organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: chloroform) to obtain dark purple amorphous islands of 2,7-bis(2-bromoethyl)-3,8°12,18-tetramethyl-13,
17-J-n-propylporphyrin 1, 34 (j
get.

UV (JE gate nm: 397,499,533,568
,621 Reference Example 5 7.12-bis(2-bromoethyl)-3,8°13,
500 mg of 17-tetramethylporphyrin-2,18-dipropionic acid dimethyl ester was added to tetrahydro7
25 m of lithium aluminum hydride is dissolved in this solution at aO~5°C. Add j and stir at the same temperature for 20 minutes. A saturated aqueous sodium sodium chloride solution, 2d, was added dropwise to the reaction mixture over a period of 1 minute, and the precipitated insoluble matter was removed in the oven. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (developing solvent: chloroform:methanol = 1:O to 30:1).
Dark purple amorphous island-like 2゜7-bis(2-bromoethyl)
-13,17-bis(3-hydroxypropyl) -
3,8,12,18-tetramethylporphyrin 255
Get m9.

u v (, (Etg艷m: 397,499,53
1,568,6211R (Br) crn, 1
595.1425.1400.1370.1290゜1
265.1225, 1200.1105 Reference Example 6 2.18-bis(3-bromopropyl)-3,8°13
, 17-titramethyl-7.12-divinylporphyrin i, oog in N,N-dimethylformamide 20 ml
Dissolve in. To this solution, 0.75d of piperidine and 1.06m of triethylamine were sequentially added, and at 60°C
After stirring for an hour, the solvent is distilled off under reduced pressure. The obtained residue is dissolved in 100 parts of chloroform, washed with water, and then dried over anhydrous sodium 5A acid.

The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (developing solvent: chloroform: methanol =
100:1 to 10:1), dark purple amorphous crystals of 2.7.12.18-tetramethyl-13,17-
bis[3-(piperidin-1-yl)propyl]-3,
550 mg of 8-divinylporphyrin is obtained.

IR (KBr) cm-': 1B10.1430.
1370.1340.1295°1255, 1220.
1200.1150.1110 Reference Example 7 500 mg of tylamidomenporphyrin is dissolved in 10 ml of N,N-dimethylformamide. Add 0.18 d of phosphorus oxychloride to this solution at 0-5°C and stir at the same temperature for 2 hours. This reaction mixture was added dropwise to a 50% dimethylamine aqueous solution 207 at 0 to 5° C. over a period of 10 minutes, and then stirred using a rod for 2 hours. Then, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 100 rdl of chloroform. After adding 100 ml of water to this solution and adjusting the pH to 1.5 with 3N hydrochloric acid, the organic layer was separated. The separated precipitate layer is washed with a saturated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (developing solvent: chloroform:methanol-1:O to 10:1
), dark purple amorphous crystalline 7,12-diethyl-3,8,13,17-titramethylborphyrine-2°18-dipropionic acid dimethylamide 250m! 9
get.

IR (KBr) cm-1; 1610.1440.1
395 Example 1 Hydrochloride (1) 7.12-bis(2-bromoethyl)-3°8, 13.17-titramethylborphyrine-2,18
- 2.979 d of dibropionic acid dimethyl ester, 1.95 d of piperidine and 2.75 d of triethylamine in N
, N-dimethylformamide 607, and the solution was stirred at 60 to 70°C for 5 hours, and then the solvent was distilled off under reduced pressure. The resulting residue is dissolved in 300 ml of chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (developing solvent: chloroform:
When purified with methanol (40:1), dark purple amorphous islands of 3.8.13.17-titramethyl-7.12-bis[2-(piperidin-1-yl)ethyl]porphyrin-2.18-dipropion were obtained. Acid dimethyl ester 1゜2
Get 29.

(2) The compound obtained in the above (1) is dissolved in a mixed solvent of chloroform-tetrahydrofuran <1:1)5(7!), and hydrogen chloride gas is introduced into this solution.

The solvent was distilled off under reduced pressure, and the resulting solid was washed with diethyl ether and dried over phosphorus pentoxide to give dark purple amorphous crystals of 3.8.13.17-titramethyl-7.1.
2-bis[2-(piperidin-1-yl)ethyl]porphyrin-2.18-dipropionic acid dimethyl ester hydrochloride is obtained.

uv (λE league) nm; 399,498,533
,568,621IR(KBr) cm”: 172
5.1B20.1510.1430.1360°124
0.1200.1165.1120 Similarly, Table-2
and the compounds shown in Table 3 are obtained.

In addition, R1 in Table-2 and Table-3 is, respectively,
The substituent of the compound represented by the following formula: is shown.

(Margin below) and Table 2 Example 2 Table 3 7,12-bis(2-bromoethyl)-3,8゜13,
17-Titramethylporphyrin-2,18-dipropionic acid dimethyl ester 230 ME! is dissolved in NN-dimethylformamide 4.6. Add 4-
Sodium salt of ethyl-2,3-dioxopiperazine 4
Add 10mff and stir at 50°C for 12 hours. After sequentially adding 40 ml of chloroform and 20 ml of water to the reaction mixture and adjusting the pH to 1.5 with 6N hydrochloric acid, the organic layer was separated. The separated organic layer is washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (developing solvent; benzene: ethyl acetate: methanol = 1 = 1: O ~ 10: 1
0:3), a dark purple amorphous product of 7,
12-bis[2-(4-ethyl-2,3-dioxopiperazin-1-yl)ethyl] -3,8,13,17-
30 ml of titramethylborphyrine-2,18-dipropionic acid dimethyl ester are obtained.

UV (JE league) nm; 400,499,531,56
8,6211R (Br) cm-1: 1730.1
655.1605.1430.1355°1255, 1
200.1160 Compounds shown in Table 4 are obtained in the same manner.

Note that R1 in Table 4 represents a substituent of the compound represented by the following formula:

Example 3 7.12-bis(2-hydroxyethyl)-3°3,1
3.17-titramethylporphyrin-2,18-dipropionic acid dimethyl ester 500 mg, 1°2.4
-Triazole 220! nl, triphenylphosphine 840 mga and diethyl azodilypoxylate 0
．． 50d is dissolved in 20 ml of tetrahydrofuran and the solution is stirred at room temperature for 17 hours. The solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 50 d of chloroform. This solution is washed with a saturated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (
Developing solvent: Chloroform: Methanol = 1:O~50:
If purified by 1), dark purple amorphous islands of 3.3.13.
17-titramethyl-7.12-bis[2-(1,2,
4-Triazol-1-yl)ethyl]porphyrin-
8 omg of 2,18-dipropionic acid dimethyl ester is obtained. When this compound is reacted with hydrogen chloride gas in the same manner as in Example 1, a dark purple amorphous island of 3°8, 13.1
7-titramethyl-7.12-bis[2-(1,2,4
-triazol-1-yl)ethyl]porphyrin-2
, 18-dipropionic acid dimethyl ester hydrochloride is obtained.

UV (2”) nm: 400,499,532
,569,622IR(KBr) cm-1; 172
5.1600.1495.1425.1340°126
5,1200.1160.1135.1100 Example 4 3,3.13.17-titramethyl-7.12-bis[
2-(Piperidin-1-yl)ethyl]porphyrin-2,18-dipropionic acid dimethyl ester aomg is dissolved in tetrahydrofuran 4d.

Add 0.8ml of 6N hydrochloric acid to this solution. After stirring for 24 hours, the solvent was distilled off under reduced pressure. The resulting residue was washed with diethyl ether and then dried over phosphorus pentoxide to give dark purple amorphous islands of 3,8°13,17-titramethyl-7,12-bis[2-(piperidine-1-
) ethylcoborphyrin-2゜18-dipropionic acid hydrochloride ttomy is obtained.

uv (λE league) nm; 397,498,530,
568,622IR (KBr) cm”: 1710
．． 1505.1440.1370.1320゜1140
, 1120 Similarly, the compounds shown in Table 5 are obtained.

Note that R1 in Table 5 represents a substituent of the compound represented by the following formula:

Table 5 Example 5 Umbrella: Hydrochloride/hydrochloride 3,8.13.17-titramethyl-7.12-bis[
2-(piperidin-1-yl)ethyl]porphyrin-2,18-dipropionic acid dimethyl ester 820 mg
is dissolved in 8 parts (7 parts) of tetrahydrofuran.

Add lithium aluminum hydride to this solution.
Add and stir at the tip for 30 minutes. A saturated aqueous sodium sulfate solution (1.57 g) was added dropwise to the reaction mixture over a period of 1 minute.
The precipitated insoluble matter is removed. The solvent was distilled off under reduced pressure,
The resulting residue was purified by column chromatography (developing solvent: chloroform:methanol = 10:1 to 5:1) to obtain dark purple amorphous islands of 2.18-bis(3-hydroxypropyl)-3, 600 mg of 8,13,17-titramethyl-7.12-bis[2-(piperidin-1-yl)ethylcoborphyrine are obtained. When this compound is reacted with hydrogen chloride gas in the same manner as in Example 1, dark purple amorphous islands of 2,18-bis(3-hydroxypropyl)-3,3,13,17-titramethyl-7,12
-Bis[2-(veridin-1-yl)ethylcoborphyrin hydrochloride is obtained.

uv (λ”=0) nm: 398,497,53
0,568,6211R (Br) cm-1: 16
00.1505.1430.1220.1140115 Compounds shown in Table 6 are obtained in the same manner.

In addition, R1 in Table 6 is the following formula: % formula %) The substituents of the compound represented by are shown below.

Example 6 2.18-bis(3-hydroxypropyl)-3°8,
13.17-Titramethyl-7.12-bis[2-(piperidin-1-yl)ethylcoborphyrin 250.7
1 g was dissolved in pyridine 5 (7). To this solution was added 0.13 d of methyl isocyanate, and after refluxing for 5 hours,
The solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: chloroform:methanol = 20:1 to 5:1) to obtain dark purple amorphous crystals of 2.7.12.18-tetramethyl-13,17. -bis[3-(N-methylcarbamoyloxy)propyl
140 mg of -3,8-bis[2-(piperidin-1-yl)ethylcoborphyrin are obtained. When this compound is reacted with hydrogen chloride gas in the same manner as in Example 1, dark purple amorphous crystals of 2.7.12.18-tetramethyl-13°17-bis[3-(N-methylcarbamoyloxy) ) Propyl J-3,8-bis[2-(piperidin-1-yl)ethylcoborphyline hydrochloride is obtained.

U V (a E=) rim: 396,498,5
31,569,622IR(KBr) cm”: 1
680. t630.1600. t510. t43
5゜1420, 1255.1185.1140.112
Compounds shown in Table 7 are obtained in the same manner as in Example 0.

Note that R1 in Table 7 represents a substituent of the compound represented by the following formula:

Table 7 Example 7 (blank below) 2.18-bis(3-hydroxylpropyl)-3, 8
, 13, 17-Chitramejiru 7.12-Bis[2-(
Morpholin-1-yl)ethylcoborphyline 120m
y is methylene chloride 2072 and N,N-dimethylformamide! Dissolve in a mixed solvent of M.

To this solution, 620 mg of 85% sodium cyanate and 1.25 d of trifluoroacetic acid were sequentially added, and the
Stir for an hour. After adding 10 d of water to the reaction mixture and adjusting the DH to 7.0 with a saturated aqueous sodium bicarbonate solution, the organic layer was separated. The separated organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.

The resulting residue was purified by column chromatography (developing solvent: chloroform:methanol = 30:1 to 20:1) to obtain 2.1a-bis(3-
Carbamoyloxypropyl)-3゜3, 13.17-
titramethyl-7.12-his[2-(morpholine-1
-yl)ethylcoborphyrin 130 tng. If this compound is reacted with hydrogen chloride gas in the same manner as in Example 1, a dark purple amorphous product of 2,18-bis(3-
carbamoyloxypropyl) -3,8,13,17
-Titramethyl-7.12-bis[2-(morpholine-
1-yl) ethylcoborphyline hydrochloride.

uv (λE edict'j) nm: 397,498.53
1,569,622IR (KBr) cm”: 17
05.1600.15i5.1450.1400゜13
30, 1260.1240.1120.1080 Example 8 layer 2.18-bis(3-hydroxypropyl)-3゜3,
13.17-Titramethyl-7.12-bis[2-(piperidin-1-yl)ethylcoborphyrine 50mg to pyridine 13mf! Dissolve in. Thionyl chloride o and ioi were added to this solution under water cooling, and after stirring at the same temperature for 15 minutes, the solvent was distilled off under reduced pressure. The obtained residue was poured into chloroform for 10rnf! After dissolving in and washing with water,
Dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (developing solvent: chloroform:methanol = 50:1-2021).
), a dark purple amorphous product of 2.18-bis(
3-Chloropropyl)-3,8,13,17-titramethyl-7.12-bis[2-(piperidin-1-yl)ethylcoborphyrin 30ffiff is obtained. If this compound is reacted with hydrogen chloride gas in the same manner as in Example 1, dark purple amorphous islands of 2,18-bis(3-chloropropyl)-3,8,13,17-titramethyl-7.1
2-bis[2-(piperidin-1-yl)ethylcoborphyline hydrochloride is obtained.

LJV (,2Etgsu)nm; 397,498,
530,568,622JR (KBr) cm”:
1605.1510.1430.1230.1140゜Example 9 1115 IR (Br) cm"1: 1730.1670.1
430.1390.1340゜1265, 1230.1
165 Example 10 2.7-bis(2-bromoethyl) -13,17-bis(3-hydroxypropyl) -3,8,12゜18
- 200 mg of tetramethylporphyrin and 290 mg of the potassium salt of 4-methyl-2,6-dioxopiperazine
The reaction was carried out in the same manner as in Example 7, and the resulting residue was purified by column chromatography (developing solvent: chloroform:methanol = 12:1) to obtain dark purple amorphous islands of 2,18- Bis(3-hydroxypropyl)-3,8,13,17-tetramethyl-7,12-
95 m3 of bis[2-(4-methyl-2,6-sioxopiverazin-1-yl)ethylcoborphyrin are obtained.

2, 7. i2.18-tetramethyl-13,17-bis[3-(piperidin-1-yl)propyl]-3゜8
- Dissolve 300 ml of divinylporphyrin in 10 d of formic acid. Add 0.6rd methyl methacrylate to this solution.
and 60 mg of 5% palladium-carbon (catalyst) were added one after another, and after stirring at 50'C under 1 atm hydrogen atmosphere for 5 hours, the catalyst was removed. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (developing solvent: chloroform:methanol = 20:1) to obtain dark purple amorphous crystals of 2,7-dinityl 3.8. 12.18-
Tetramethyl-13,17-bis[3-(piperidine-
1-yl)propylcoborphyrin 180m,9 is obtained. If this compound is reacted with hydrogen chloride gas in the same manner as in Example 1, dark purple amorphous crystals of 2,7-dinityl-3
．． 8.12゜18-tetramethyl-13,17-bis[
3-(Piperidin-1-yl)propylcoborphyrin hydrochloride is obtained.

Uv(λE)nm; 394,497,530,5
68,622IR(KBr) cm-1: 1600.
1510.1440.1370.1145 Similarly,
The compound shown in Table-8 is obtained.

In addition, R2 in Table 8 is the following formula: % formula %) The substituents of the compound represented by are shown below.

Example 11 230 m3 of 7,12-diethyl-3,8,13,17-titramethylborphyrine-2,18-dipropionic acid dimethylamide was mixed with 107 m3 of tetrahydrofuran! Dissolve in. Add 70ml of lithium aluminum hydride to this solution.
g and refluxed for 2 hours, then cooled on ice. 1 ml of a saturated aqueous sodium sulfate solution was added dropwise to the reaction mixture over a period of 1 minute, and the precipitated insoluble matter was removed.

The solvent was distilled off under reduced pressure, and the resulting residue was washed with diethyl ether and dried over phosphorus pentoxide to give dark purple amorphous islands of 2,18-bis[3-(N,N- dimethylamino)propyl]-7.12-diethyl-3,3,1
160 m$ of 3,17-titramethylborphyrine is obtained. If this compound is reacted with hydrogen chloride gas in the same manner as in Example 1, dark purple amorphous islands of 2,18-bis[3-
(N,N-dimethylamino)propyl]-7.12-diethyl-3,8°13,17-titramethylborphyrine hydrochloride is obtained.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ “In the formula, R^1 is a hydrogen atom, a lower alkylamino group,
a di-lower alkylamino group or an optionally substituted nitrogen-containing heterocyclic group bonded via the nitrogen atom in the ring; R
When R^1 is a hydrogen atom, ^2 is a lower alkylaminomethyl group, a di-lower alkylaminomethyl group, or the formula -CH_2R^3 (wherein, R^3 is a bond via a nitrogen atom in the ring). (optionally substituted nitrogen-containing heterocyclic group); Also, a substituent in which R^1 is bonded via a lower alkylamino group, a di-lower alkylamino group, or a nitrogen atom in the ring. R^2 is a nitrogen-containing heterocyclic group which may be substituted with a methyl group, a hydroxymethyl group, a carboxyl group, a lower alkoxycarbonyl group, a halogenomethyl group, or a lower alkyl or aryl group. This represents a good carbamoyloxymethyl group. ” Porphyrin derivatives and salts thereof.