A complex salt of hematoporphyrin and its derivatives, a mixture of complex salts of hematoporphyrin and its derivatives, the method of obtaining complex salts, the method of obtaining a mixture of complex salts, pharmaceutical composition

 

(57) Abstract:

New complex salts of hematoporphyrin and its derivatives of the formula I, in which R1and R2the same or different and represent a group-CH=CH2, -CH(OH)CH3, -CH-(OR3)CH2where R3group forming oligomer containing ether or ester composed of 1 to 5 identical or different units, or R1and R2denote CHR4CH3(the values of R4see p. 1 formula): A - amino acid core: m = 2-4, n = 1-5. The method of obtaining complex salts 1 based on the reaction of hematoporphyrin derived from basic amino acid. Compounds 1 are used as a means for the detection and treatment of tumors. 5 C. and 7 C.p. f-crystals, 5 tab., 6 Il.

A complex salt of hematoporphyrin and its derivatives, a mixture of complex salts of hematoporphyrin and its derivatives, the method of obtaining complex salts, the method of obtaining a mixture of complex salts, pharmaceutical composition.

The object of the invention is a complex salt of hematoporphyrin and its derivatives, method for their production and pharmaceutical means. New salt of hematoporphyrin and its derivatives are used for the s (HpD) is used as photosensitizers for the detection and destruction of tumors in humans and animals. Connection these are served in intravenous injections and they are transported by active transport to different organs of the body. In healthy tissue, are they a relatively short period, as they are metabolized and excreted, but in tumor tissue they are accumulated and at almost unchanged level remain for several days. This was used in the photodynamic method of diagnosis and selective destruction of tumor tissue. Since all derivatives of hematoporphyrin difficultly soluble in water, the method of preparation of their water solutions was still very heavy.

B Cancer Research volume 44, pages 1924, 1984(see the same volume 45, page 635, 1985) described a method of obtaining hematoporphyrin drugs for injection. It is that hematoporphyrin derivatives dissolved in the NaOH solution, mix one hour and after naturalizirujut to pH of about 7.1 and titration with 0.1 N HCl. This method is very inconvenient, as in the case of small transition pH below 7 is precipitation. The final solution is prepared by adding the appropriate amount of physiological salt. The solution is sterilized and stored in closed vials. Such preparations in the form of water solutions of unstable due to a large handstory remain stable for about 3 months, provided what they should be stored in dark and cool place (at a temperature of -20oC).

The subject invention is a new, water-soluble complex salt of hematoporphyrin and its derivatives, which, depending on concentrations give a pH from 7.2 to 7.8, which gives the ability to quickly produce a solution soluble in water or in physiological salt and get the best bioavailability of therapeutic agents. It was unexpectedly found that the new complex salts are more therapeutic activity than, for example, known sodium salt of hematoporphyrin and its derivatives (HpD Na2). In addition, new salt detained without irradiation cell growth of tumors, which was confirmed in studies on cell lines. According to the invention salts of hematoporphyrin and its derivatives have the General formula I (Fig. 1) in which R1and R2the same or different and represent a group-CH=CH2, a group-CH(OH)CH3, a group-CH(OR3)CH3where R3refers to a group creating oligomer containing the relationship ether and/or ester composed of 1 to 5 identical or different units derived from the monomer according to formula II (Fig. 2), or R1and R2identical and denote GRU is Boxing-2-methylpropylamine, 1-carboxy-3-methyl-butylamino, 1-carboxy-2-methyl-butylamino, 1-carboxymethylamino, 1-carboxymethylamino, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxy-propylamino, 1-carboxy-2-mercapto-ethylamino, 1-carboxy-3-methylthiopropionate, 1,2-dicarboximido, 1-carboxy-2-carbamoylation, 1,3-dicarboxyphenoxy, 1-carboxy-3-carbamoylbiphenyl, 1-carboxy-2-phenyl-ethylamino, 1-carboxy-2-(4-hydroxyphenyl)-ethylamino, 1-carboxy-2-indolylmaleimide, 2-carboxypropanoyl, 2-carboxy-4-hydroxypyridine, 1-carboxy-5-amino-pentylamine, 1-carboxy-4-guanidyl-butylamino, 1-carboxy-4-hydroxy-5-amino-pentylamine or group 1-carboxy-2-(1H-imidazol)-ethylamino. And indicates a basic amino acid, m is equal to 2 to 6, n is equal to 1-5. In the scope of the invention are also mixtures of salts of formula I and complexes of these salts. Best amino acid symbol A is amino acids, whose isoelectric point is more than 7, mainly arginine, lysine, histidine or hydroxylysine. Best salt is a salt of formula I, in which R1and R2the same and represent the group-CH(R4)-CH3. Examples of salts of formula I are salts of ether is camping amino acid salt of hematoporphyrin, protoporphyrin, vinyltetrahydrofuran and dihematoporphyrin ether and possibly their units.

A method of manufacturing a new complex salts of hematoporphyrin and its derivatives of General formula I or mixtures of salts of the General formula I, in which the symbols have the above significance, according to the invention is based on the fact that hematoporphyrin derivative of General formula IV (Fig. 4) or a mixture of at least two derivatives of the General formula IV in which R1and R2have videodance value, so that if R1and R2represent a group-CH(R4)-CH3then the carboxyl group of the substituent R4can be free or protected, is subjected to reaction with a basic amino acid in free or protected carboxyl groups or with his monochlorotoluenes salt, advantageously in an organic solvent, in a mixture of organic solvents or in a medium containing an organic solvent and water or a mixture of organic solvents and water, or eliminate group protecting the carboxyl function and isolate the product represents the salt of formula I or a mixture of salts of formula I, or salts containing aggregates of the formula I. In the process according to the invention the reaction of the amine groups of the amino is>-COOH+H2N-R _ -COO-+H3N-R.

As the basic amino acid is used amino acids with isoelectric point of >7, especially arginine, lysine, histidine or hydroxylysine.

For the protection of carboxyl groups in the source compounds is possible to use various known blocking groups, for example as described in Protective Groups in Organic Synthesis, T. W. Green, John Wilex and Sons, 1981. Examples of these groups are groups forming esters alkyl, benzyl, Silovye, and other groups used to provide carboxyl functionality. The reaction can occur in a wide range of temperatures, advantageously in the range from room temperature to 100oC, especially at a temperature of 50-70oC. the reaction Time is usually from several minutes to more than ten hours.

Best organic solvents is amides, such as formamide, dimethylformamide, diethylformamide; nitrides, such as acetonitrile, propionitrile, isobutyronitrile; esters, such as ethyl acetate; ketones such as acetone; sulfoxidov, for example, dimethylsulfoxide; alcohols and wholistically ether or mixtures thereof. Usually, the reaction is carried out in an aqueous-organic medium.

Blocking groups, if they prisutstvie the mixture of salts with formula I can be isolated from the reaction mixture by different methods, for example, precipitation, crystallization, and other known methods.

Particularly advantageous method is based on the fact that until the reaction mixture is added to the solvent or mixture iskopaemykh solvents such, however, that with the solvent used for the reaction, to form a homogeneous solution with a ratio of from 1:1 to 1:5. Appropriate solvents are, for example, ethyl ether, acetone. The resulting mixture was left for a few (up to more than ten hours for the slow precipitation of the product. The residue after filtration and promite dried in vacuum over a drying agent, it is advantageous P2O5. It is stable and does not dissolve in the air. The compounds need to be protected from light. Stage selection contains a possible separation of the mixture.

The parent compound with the formula IV are known. You may obtain them from hemin.

The subject of the invention is also a pharmaceutical tool for the detection and/or treatment of tumors containing salt with General formula I in which the symbols have the above significance, or a mixture of at least two salts of the formula I or their aggregates. A sample mixture is a mixture containing the amino acid salt of hematoporphyrin, protoporphyrin, wine is t to be salt according to formula I or a mixture of salts according to formula I in the form of a solid body, advantageously located in a sterile, tight container.

Sterile, tight container usually contains salt or mixture of salts in a therapeutically effective dose. Therapeutic effective dose is typically 1.5-10 mg/kg of body weight. Of salt in the container, you can very quickly produce sterile water solutions for direct extraintestinal feed.

The tool according to the invention can also be manufactured in the form of drugs, ready to use. In this case, the active substance, i.e. salt or mixture of salts according to formula I, is mixed with a pharmacologically acceptable diluent and/or carrier. Usually the tool is supplied by injection, mainly internal, although it can also be applied intraperitoneally or inside the rectum. Sample preparation is a sterile water solution. A water solution, except salt according to formula I, contains the possible physiological salt and if necessary - propylene glycol.

As already mentioned, such solutions can be applied directly after their production or they can be stored in sterile containers. The tool according to the invention can be applied without exposure, however, is more effective and shows Obedinenie by the formula I were investigated in cell lines. Research used 9-10 different cell lines and tumors that were incubatory for 48 h with different salts of derivatives of protoporphyrin and with the new salt drug used HpD (hematoporphyrin derivatives) obtained by the method of Lipson and employees.

All test compounds were applied in the form of water solutions. They were applied at a concentration of 50 µg/ml.

Were investigated and defined:

1) fluorescence F cells after 48-hour incubation, cells were washed and examined the intensity of fluorescence in fluorescencia microscope, defining it in an arbitrary scale from 0 to 4;

2) was determined (P%) - the percentage of living cells after a predetermined time of incubation;

3) was determined by the multiplication factor M cells under the influence of certain drugs, defining it in the following way:

M = the number of times the cells in culture with drug concentration of 50 μg/ml after 48 h/the number of times the cells in the control culture after 48 hours

The results of the studies are given in tables 1-3.

From the data presented in tables 1-3, it is seen that the compounds with the formula I have a different affinity for the studied cleoc the AMB derivative, the most active for this type of tumor that extends the capabilities of effective therapy.

The list used in tables 1-3 characters cell lines used in studies anticarcinogenic drugs, derivatives of protoporphyrin and drug HpD:

Hep - 2 cells of laryngeal cancer

Hela cells cervical cancer

KB - cell cancer of the oral cavity

HBT-39/w cancer cells nipple

T-47D cells cancer nipple

P3HR1 cells of limpach Burkitt

GLCH - small cell lung cancer

Line murine tumors:

GR MT/F6 - cancer cells of the nipple mouse strain GR

Mm5MT/Cl - cancer cells of the nipple mouse strain C3H

MA-104 - cancer cells of the embryo kidney rhesus monkeys

In comparison with known drug HpD new salts have a wider limit penetration of different types of cancer cells and the best efficiency of their destruction.

About using the new arginine salt HpD(HpD Ag2) the percentage of living cells after 48 h of incubation (P%) for line Hela equal to 13, the line MA-104 is equal to 6; for line HBT-39/w is equal to 0, in the case of application of the known drug, i.e., sodium salt HpD(HpD Na2), the values many times greater and equal: for line Hela - 28; for the line MA-104 - 17; for active in the test cell line Mm5MT/Cl - cancer of the nipple mouse strain C3H - i.e., PP(Lyz)2(Arg)2(compound of example XXI) and the least active for this type of cancer, i.e., PP(Glu)2(Arg)2(compound of example XIX).

Research produced in mice C3H transplantirovannam cancer of the nipple when feeding both compounds at a dose of 10 mg/kg and in two versions. Animals were irradiated with a laser He-Ne in portion 150 J/cm2that is marked with the letter L at the symbol connection in the diagram (Fig. 6), and in another embodiment they were not irradiated.

The diagram shows in graph form the results obtained. They showed that:

1) results of studies on cell lines were confirmed in animal studies,

2) product PP(Liz)2(Arg)2was an active and much continued accommodation of the test animals,

3) amino acid derivatives of protoporphyrin are cytotoxic to cancer cells, not too excited by laser light, although weaker than under the influence of the laser.

Example I. HpD is a mixture of hematoporphyrin derivative, such as hematoporphyrin, protoporphyrin, vinyldithiins, dihematoporphyrin ether and their aggregates. 1 g HpD molecular weight 600 (1,67 mmol) dissolved the 5-20 minutes at a temperature of 60oC in a water bath, intensively mixing. Then added 100 ml of acetone and the mixture was stirred for about 3-5 minutes the Solution was left at rest for 5-15 hours At this time was deposited sediment mixture of salts, denoted by HpD(Arg)2. The precipitate was filtered, washed with ether and dried in vacuum. After drying in vacuum, the residue is resistant to air and should be protected from light because included in it porphyrin derivatives. The reaction takes place with a yield of about 75%.

Example II. 1 g HpD dissolved in 20 ml of formamide and added 581,8 mg of arginine dissolved in 2 ml of H2O. the Solution was heated and mixed as in example 1. Then, after cooling, was added 100 ml of ethyl ether. The solution was stirred and left alone for a few hours. After filtration and washing with ether, the precipitate was dried in vacuum.

Received to 126.8 mg sludge mixtures of salts HpD(Arg)2that corresponds to a yield of 86%.

Example III. 1230 mg dieselmotoren PPLiz2(1.4 mmol) dissolved in 40 ml of formamide and mixed with 490 mg of 1-arginine (2.8 mmol) dissolved in 1.5 ml of water. The mixture was heated at a temperature of 60oC in a water bath for about 20 minutes received from life After cooling 100 ml of ethyl ether, mixed and left to a few%. Data of the obtained compound shown in example XXI in table 4.

Example IV. 1199,6 mg (1.4 mmol) of dglucopyranosyl dissolved in 60 ml of formamide and added 409,3 mg 1-lysine dissolved in 1.5 ml of water. The mixture was heated for 30 min at a temperature of 60oC, then added 120 ml of acetone-ether mixture with ratio 1:3 (30 ml acetone, 90 ml of ethyl ether), mixed for another 10 min, and then was left alone for a few hours. Then was filtered in vacuum, washed with ethyl ether and dried in vacuum over P2O5. Received 1575 mg of product, which corresponds to 97.8% of the resultant theoretical output.

Example V. 1081,8 mg (1.4 mmol) of diarylpropionitrile dissolved in 50 ml of formamide and added 490 mg of 1-arginine (2.8 mmol) dissolved in 1.5 ml H2O. the Mixture was heated at a temperature of 60oC for 30 min, then added 120 ml of acetone-ether mixture with ratio 1:3 (30 ml of acetone and 90 ml of ethyl ether and all mixed up another 50 minutes

The solution is left to crystallize for several hours. Then, the deposited precipitate was filtered under vacuum and Susan in vacuum over P2O5. Received 1500 mg of sediment, i.e. 95,5%. In a similar fashion as described in example V, obtained all CE 5 are compounds of the formula I, where A=arginine, m = 2, n = 1, R1=R2=-CH(R4)-CH3where R4see table. 5.

Example XXVI.

To 1037,12 mg (1.4 mmol) of di-(N-alanyl)protoporphyrin dissolved in 40 ml of dimethylformamide, add 434,4 mg (2.8 mmol) of histidine dissolved in 3 ml of water. The mixture is heated for 40-50 min in a water bath with vigorous stirring. After cooling, add 100 ml of a mixture of acetone-ether (1:3). The mixture is then stirred for about 10 min and allow to settle for several hours. After filtration under vacuum and vacuum drying over P2O5the resulting product is a salt of histidine - 1353 mg, which corresponds to a yield of 92%.

Range of UV vismaxnm/208/histidine/, 400, 514, 550, 570, 632.

1. A complex salt of hematoporphyrin and its derivatives having the General formula I

< / BR>
in which R1and R2the same or different and represent a group-CH=CH2, a group-CH(OH)CH3, a group-CH(OR3)CH3where R3denotes a group forming oligomer containing ether and/or ester composed of 1 to 5 identical or different units derived from the monomer with formula 2, or R1and R2the same and represent the group-CH(R4) - CH3where R1-carboxy-2-phenyl-ethylamino, 1-carboxy-2-methyl-propylamino, 1-carboxy-3-methyl-butylamino, 1-carboxy-2-methyl-butylamino, 1-carboxy-butylamino, 1-carboxy-pentylamine, 1-carboxy-2-hydroxy-ethylamino, 1-carboxy-2-hydroxy-propylamino, 1-carboxy-2-mercapto-ethylamino, 1-carboxy-3-mutilatio-Propylamine, 1,2-dicarboxy-ethylamino, 1-carboxy-2-carbamoyl-ethylamino, 1,3-dicarboxy-propylamino, 1-carboxy-2/4-hydroxy phenyl/-ethylamino, 1-carboxy-2-indolyl-ethylamino, 2-carboxy-pyrrolidinone, 2-carboxy-4-hydroxypyridine, 1-carboxy-5-amino-pentylamine, 1-carboxy-4-guanidinonaltrindole, 1-carboxy-4-hydroxy-5-aminophenylamino or group 1-carboxy-2-/1H-imidazole/-ethylamino;

A denotes a basic amino acid;

m = 2 to 4;

n = 1 - 5.

2. Salt p. 1, wherein A stands for arginine, lysine, histidine or hydroxylysine.

3. Salt p. 1, wherein R1and R2the same and represent the group-CH(R4)CH3.

4. Salt PP.1 to 3, characterized in that m = 2; n = 1.

5. A mixture of complex salts of hematoporphyrin and its derivatives containing salt hematoporphyrin, protoporphyrin, vinylcyclopentane and dihematoporphyrin its derivatives of General formula I, in which R1and R2the same or different and represent a group-CH= CH2group-CH/OH/CH3group-CH/OR3/CH3where R3denotes a group forming oligomer containing ether and/or difficult-air, composed of 1 to 5 identical or different units deriving from monomers according to formula II

< / BR>
or R1and R2the same and represent the group-CH/R4/ - CH3where R4denotes a group of the carboxy-metilenovuju, 1-carboxy-ethylamino, 1-carboxy-2-methylpropylamine, 1-carboxy-3-methyl-butylamino, 1-carboxy-2-methyl-butylamino, 1-carboxy-butylamino, 1-carboxy-pentylamine, 1-carboxy-2-hydroxy-ethylamino, 1-carboxy-2-hydroxy-propylamino, 1-carboxy-2-mercapto-ethylamino, 1-carboxy-3-mutilatio-Propylamine, 1,2-dicarboxy-ethylamino, 1-carboxy-2-carbamoylation, 1,3-dicarboxy-propylamino, 1-carboxy-3-carbarnoyl-propylamino, 1-carboxy-2-phenyl-ethylamino, 1-carboxy-2/4-hydroxyphenyl/-ethylamino, 1-carboxy-2-indolyl-ethylamino, 2-carboxy-pyrrolidinone, 2-carboxy-4-hydroxypyridine, 1-carboxy-5-amino-pentylamine, 1-carboxy-4-guanidyl-butylamino, 1-carboxy-4-hydroxy-5-amino-Penta is R>
m = 2 to 4;

n = 1 to 5

characterized in that hematoporphyrin derivative with the General formula IV

< / BR>
in which R1and R2have the above specified value, so that if R1and R2represent a group-CH/R4/-CH3then the carboxyl group of the substituent R4can be free or protected,

subjected to interaction with basic amino acid in free or protected carboxyl groups or its monochlorohydrin or eliminate groups that provide carboxyl functionality and produce the product, which is the salt of formula I.

7. The method according to p. 6, characterized in that the reaction is carried out in an organic solvent, in a mixture of organic solvents or in a medium containing an organic solvent and water or a mixture of organic solvents and water.

8. The method according to p. 6, characterized in that in the form of amino acids are used arginine, lysine, histidine or hydroxylysine.

9. The method according to p. 6, characterized in that the salt emit add to the reaction mass iskopaemye solvent or mixture of solvents, forming a homogeneous solution with the solvent used in the reaction.

10. The method of obtaining the cm shall hirin and dihematoporphyrin ether, subjected to interaction with basic amino acid.

11. Farmcampsite for the diagnosis and/or treatment of tumors, comprising operating means on the basis of hematoporphyrin and a carrier, wherein the active means it has a connection on p. 1 of General formula I (where R1, R2, A, m, n have the above for p. 1 values), in an effective amount.

12. Farmcampsite for the diagnosis and/or treatment of tumors on p. 11, characterized in that as the current tools it contains a mixture of salts of hematoporphyrin, protoporphyrin, vinylcyclopentane and dihematoporphyrin ether with a basic amino acid in an effective amount.

 

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EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

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EFFECT: enhanced effectiveness of treatment.

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4 cl

FIELD: medicine.

SUBSTANCE: method involves applying transscleral diaphanoscopic examination method for adjusting intraocular neoplasm localization and size. Rectangular scleral pocket is built 2/3 times as large as sclera thickness which base is turned from the limb. Several electrodes manufactured from a metal of platinum group are introduced into intraocular neoplasm structure via the built scleral pocket. Next to it, intraocular neoplasm electrochemical destruction is carried out in changing electrodes polarity with current intensity of 100 mA during 1-10 min, and the electrodes are removed. Superficial scleral flap is returned to its place and fixed with interrupted sutures. 0.1-2% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transpupillary laser radiation of 661-666 nm large wavelength is applied at a dose of 30-120 J/cm2. the operation is ended with placing sutures on conjunctiva. Platinum, iridium or rhodium are used as the metals of platinum group. The number of electrodes is equal to 4-8. 0.1-1% khlorin solution, selected from group containing photolon, radachlorine or photoditazine, is additionally repeatedly intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2.

EFFECT: complete destruction of neoplasm; excluded tumor recurrence; reduced risk of tumor cells dissemination.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

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