The method of obtaining the derivative of hematoporphyrin

 

(57) Abstract:

Usage: chemistry of biologically active compounds. The essence: gaining derived hematoporphyrin ("Photohem") are consistent treatment of hemin 50%. a solution of hydrogen bromide in acetic acid, sodium acetate and 0.05-0.1 N solution of sodium hydroxide with subsequent deposition of the lower alcohol (C1-C3). 11 Il., table 2.

The invention relates to the chemistry of biologically active compounds, and specifically to an improved process for the preparation of a derivative of hematoporphyrin, which is used as a photosensitizer for photodynamic therapy (PDT) of malignant tumors.

Hematoporphyrin derivatives is a complex semi-synthetic mixture of Monomeric and oligomeric porphyrins, and active in this mixture are oligomeric components.

A method of obtaining a derivative of hematoporphyrin(GWP), which includes the sequential processing of hematoporphyrin [1] a mixture of acetic and sulfuric acid (19:1) and alkali and subsequent enrichment of the oligomers using membrane filtration [2]

The disadvantages of this method include the following:
the ina, which reacts with alkaline treatment, produces by-products (monoacetate of hematoporphyrin and hematoporphyrin), which reduces the degree of oligomerization in the final product;

2) the enrichment method GWP oligomeric fraction using membrane filtration laborious and time consuming operation during which the composition of the GWP may change, which complicates its standardization.

The aim of the invention is to simplify the process of obtaining the derivative of hematoporphyrin and increase the content of active oligomeric fraction.

This goal is achieved in the following way.

Geminus is treated with 50% solution of hydrogen bromide in acetic acid (at a lower concentration is required to take large quantities of a solution of hydrogen bromide in acetic acid, and at high concentrations it is difficult to work because of the rapidly released HBR), added sequentially acetic acid, fused sodium acetate and water. Fallen hematoporphyrin diacetate is filtered and treated with 0.05 to 0.1 N sodium hydroxide solution for 1 hour (when the alkali concentration more About, 1N decreases the degree of oligomerization, and when the concentration of men who UltraVivid, washed with water, mixed with a lower alcohol (C1-C3within 20 hours (Monomeric porphyrins preimushestvenno into solution), the precipitate is filtered off, washed with alcohol and dried in the air.

Distinctive features of the proposed method are used as initial substances for the oligomerization of hematoporphyrin diacetate, and not a mixture of products atsetilirovaniya of hematoporphyrin (obtaining the latter requires more stages of the synthesis of hematoporphyrin diacetate), which leads to a reduction stages upon receipt of gypsum, on the basis of hemin, and to increase the degree of oligomerization in the final product; enrichment GWP active oligomeric components using a simple extraction of the lower alcohols under mild conditions, which eliminates adverse reactions (as is the case when using membrane filtration) and allows you to get the future drug for PDT.

Example 1. 10 g of hemin add portions to 60 g of a 50% aqueous solution of hydrogen bromide in acetic acid at -5oC, stirred for 12 hours ( until complete dissolution of hemin), add 480 ml of acetic acid, then sprinkled portions 92 g of sodium acetate, stirred for 1 hour, time is of acetate of hematoporphyrin dissolved in 250 ml of 0.1 N sodium hydroxide solution and stirred for 1 hour. Then the pH of the solution was adjusted with acetic acid to values 4-6 deposited precipitate is filtered off and washed with water. The resulting material was stirred with 250 ml of methanol for 20 hours, filtered off, washed with methanol and dried in air. Yield: 2 g

Example 3. 8 g of hematoporphyrin diacetate are dissolved in 800 ml of 0.05 N sodium hydroxide solution and stirred for 1 hour. Then the pH of the solution was adjusted with acetic acid to values 4-6 deposited precipitate is filtered off and washed with water the precipitate is stirred with 400 ml of ethanol for 20 hours, filtered off, washed with ethanol and dried in air. Yield: 3.3 g

Example 4. Hematoporphyrin diacetate is treated similarly to the second example. The precipitate is stirred with 250 ml of isopropanol for 20 hours, filtered off, washed with isopropanol and dried in air. Yield: 2.3 g

Control of the oligomeric composition of EGR is performed using chromatography on gel Fractogel HW-40(S) (Merck, Germany) in dimethyl sulphoxide, toluene-acetic acid (1:1:1). The gel chromatogram of samples GWPs shown in Fig.1-4.

The ratio of peak areas in the chromatograms, which correspond to the content monomerization using physico-chemical methods of analysis, mass spectrometry, IR and electronic spectroscopy (see tab.2, the spectra shown in Fig. 5-11). 2, 4, 6, 8, 10 TTT,

The method of obtaining hematoporphyrin derivatives with acetic acid, alkali and enrichment oligomers, characterized in that geminus sequentially treated with 50% solution of hydrogen bromide in acetic acid, sodium acetate and 0.05-0.1 N solution of sodium hydroxide with subsequent deposition and enrichment oligomers extraction of lower alcohols (C1-C3).

 

Same patents:

The invention relates to the refining, namely the production and purification of the free bases of petroleum porphyrins complexes with cobalt and iron, as well as the products of their thermal modification can find application as catalysts of oxidation-reduction processes, such as oxygen reduction [1]-[4]

Oil and products of its processing, a mixture of hydrocarbons and hetero-organic components contain only the metal complexes of porphyrins, in particular vandrove and Nickel

The invention relates to organic chemistry, in particular to an improved process for the preparation of porphyrins, in particular to a method for producing chlorin e6(18-carboxy-20-(carboxymethyl)-8-ethynyl-13-ethyl-2,3-dihyd - ro-3,7,12,17 - tetramethyl-n, n

The invention relates to an improved method for producing a 5,15-di(n-nitrophenyl)-3,7,13,17-tetramethyl-2,8,12,18 - tetrabutyltin, which can be used as activator of membrane gas separation and as an intermediate product in the synthesis of parvinzadeh poly - condensation monomers

FIELD: organic chemistry.

SUBSTANCE: invention relates to new derivatives of metalloporphyrazine of the general formula (I): wherein M means Cu, Co. These compounds can be used as dyes, catalysts in different processes and materials of sensitive members of gas sensor.

EFFECT: valuable properties of compounds.

2 cl, 6 sch, 1 dwg, 5 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to method for production of synthetic chlorophyll (Chl) or bacteriochlorophyll (Bchl) derivatives of general formula I , wherein X is O;. Claimed method includes interaction under anaerobic conditions of Chl, Bchl derivatives containing COOCH3-group in C-132-position and COOR3-group in C-172-position in presence of tetraethyl orthotitanate. Further compounds of formula I wherein R1 and R2 are different radicals are obtained in aproton solvent such as peroxide-free tetrahydrofurane and dimethyl formamide, and compounds of formula I wherein R1 and R2 are the same ones are produced by using R1OH as a solvent. Derivatives of present invention are useful as stabilizers, linkage/spacer for binding another acceptable molecules to Chl/Bchl macrocycle.

EFFECT: simplified method for production of various chlorophyll or bacteriochlorophyll derivatives.

13 cl, 3 ex, 2 tbl, 8 dwg

FIELD: microbiology.

SUBSTANCE: invention relates to method for production of porphyrinopeptides satisfying the formula I , wherein R1 and R2 independently from one another represent amino acids or peptides comprising 2-15 of amino acid residues, wherein α-carboxylic groups of amino acids or peptides may be modified by C1-C8-alkyl ester and side functional groups of amino acids or peptides may be protected; in particular R1 is ArgOMe; R2 is -OH (III); R1 is LeuHisOMe; R2 is -OH (IV); R1 is LeuLeuValPheOMe; R2 is -OH (V); porphyrin carboxylic group may be modified by methyl or other C1-C9-ester or pharmaceutically acceptable salt; Y- represents Cl-; Me represents Zn, Cu, Fe, Mn. Claimed method includes activation of porphyrin carboxylic group with N-oxy-5-norbornene-2,3-dicarboxyimede in molar ratio of 1:1 in presence of N,N'-dicyclohexylcarbodiinide; or with diphenylphosphorylazide (DPPA) in equimolar ratio of porphyrin/DPPA in presence of base. Then porphyrin with activated carboxylic group is brought into reaction with amino component (amino acid or peptide) in form of mineral acid salt, which is neutralized with base. Also disclosed are methods for application of compounds (I) as nucleotic agents.

EFFECT: new nucleotic agents.

4 cl, 7 ex, 1 tbl

FIELD: chemistry of metalloorganic compounds.

SUBSTANCE: invention relates to new derivatives of metalloporphyrazines of the general formula (I):

wherein M means Cu, Co. These compounds can be used as dyes, catalysts of different processes and material for sensitive members of gas pickups.

EFFECT: valuable properties of complexes.

4 fig, 1 dwg, 5 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: sensitizing agent for photodynamic disruption of malignant neoplasm cells represents a new compound - 18-hydroxy-substituted cycloimide of chlorine p6 or 7,8-dihydroxybacteriochlorine of the formula (I):

. Compounds of the formula (I) are used as an agent in treatment of malignant neoplasm. Invention expands assortment of sensitizing agents used in carrying out the photodynamic therapy.

EFFECT: valuable medicinal properties of agent.

6 cl, 1 dwg

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to 2,3-dicarboxy-6,7-dimethylanthraquinone of the formula (I):

that is characterized by melting point value Tm 207°C. This compound can be used as the parent substance in synthesis of metal complexes tetra(-di-6,7-carboxy)-anthraquinonoporphyrazine used as dyes and catalysts. Also, invention describes methods for synthesis and using compound of the formula (I).

EFFECT: value properties of compound and complexes.

4 dwg, 6 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to 2,3-dicarboxy-5,6,8-trimethylanthraquinone of the formula (I):

. This compound can be used in synthesis of metal complexes of tetra-(tri-5,6,8-carboxy)-anthraquinonoporphyrazine used as dyes and catalysts. Compound of the formula (I) is characterized by melting point value (Tm) 207°C. Also, invention describes methods for synthesis and using compound of the formula (I).

EFFECT: valuable properties of compound.

4 cl, 6 ex

FIELD: organic chemistry of complex compounds.

SUBSTANCE: invention relates to new derivatives of metalloporphyrazines, namely: to metal complexes of tetra-(tri-5,6,8-methyl)-anthraquinonoporphyrazine of the general formula:

. These compounds can be used as parent substances for synthesis, respectively, copper and cobalt complexes of tetra-(tri-5,6,8-carboxy)-anthraquinonoporphyrazine used as dyes, catalysts in different processes, materials in sensitive members of gas transducers.

EFFECT: valuable properties of complexes.

2 cl, 7 dwg, 8 ex

FIELD: organic chemistry of complex compounds.

SUBSTANCE: invention relates to new derivatives of metalloporphyrazines, namely to metal complexes of tetra-(tri-5,6,8-carboxy) -anthraquinonoporphyrazine of the general formula:

. These compounds can be sued as dyes, catalysts in different processes and materials for sensitive members of gas transducers.

EFFECT: valuable properties of compounds.

2 cl, 5 dwg, 6 ex

FIELD: chemistry of metalloorganic compounds, chemical industry.

SUBSTANCE: invention relates to preparing compounds of tetrapyrazinoporphyrazine order, namely, to cobalt octasulfooctaphenyltetrapyrazinoporphyrazine of the formula:

that can be used as a catalyst in oxidation reactions of sulfur-containing compounds, in particular, cysteine and thioureas, and diethylamine also being both in acid and neutral media.

EFFECT: valuable properties of compound.

2 cl, 2 dwg, 4 ex

Up!