Ureidopropionic naphthaleneboronic acids or their pharmaceutically acceptable salts and pharmaceutical compositions on their basis

 

(57) Abstract:

The compounds of formula I, where each of m and n is an integer of 1-4; p, q is an integer of 1-3; R is a free or esterified group, phosphonic acid, and their pharmaceutically acceptable salts can be used as antiuniverse funds. 2 c. and 4 C.p. f-crystals, 1 PL.

The invention relates to new ureidopropionic naphthaleneboronic acids, method for obtaining them, containing their pharmaceutical compositions and their use in medicine.

In the international application PCT/EP/00014 described ureidopropionic poly-4-amino-2-carboxy-1-methylpyrrole.

Now we have found that new derivatives naphthaleneboronic acids and narrow the selected class new naphthaleneboronic acids that are within the scope of General formula PCT/EP 91/00014, but where they are not specifically described, possess valuable biological properties.

Accordingly, an object of the present invention are new ureidopropionic naphthaleneboronic acids having the following formula (I)

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where each of m and n that have the same values, is an integer from 1 to 4; each of p and q that have the same value is free or esterified group, phosphonic acid, and pharmaceutically acceptable salts of these derivatives.

Available, converted into a salt or esterified phosphonopropyl [(HO)2PO-group] can be one or both phenyl parts (cores benzene) naphthalene group.

Substituted nattylove groups are preferably 1-, 2-, 3 - or 4-naphtylamine groups, typically 3 - or 4-naphtylamine groups. When nattylove group substituted with three free, esterified or converted into a salt of phosphonic acid groups, these phosphonic acid substituents are preferably in positions 1, 5 and 7, 2, 5 and 6 or 2, 5 and 7. When they replaced two free, esterified or converted into a salt of phosphonic acid groups, these substituents are preferably in positions 1 and 5, 1 and 6, 1 and 7 or 5 and 7. When they replaced one free, esterified or converted into a salt of phosphonic acid group, the Deputy preferably is in position 1, 3, 5, or 6. The present invention includes in its scope all the possible isomers, stereoisomers and their mixtures, and the metabolites and the metabolic precursors or bioresistant compounds of formula (I).

As indicated above, n CLASS="ptx2">

Only one or both of the two acid functions (hydroxyl groups) of each phosphonopropyl [(HO)2PO-group] can be converted into a salt and/or tarifitsirovana.

The salts of the present invention preferably only one of the two acid functions of each phosphonopropyl is in salt form, whereas the esters of the present invention, both the acid functions of each phosphonopropyl are preferably esterified form.

Esters of acids of the formula (I) are, for example, alkylamine and arylalkylamine esters with alkyl chain normal or branched structures. Preferred C1-C6-alkalemia and phenyl-C1-C6-alkalemia esters, typically methyl, ethyl, propyl, isopropyl, butyl, benzyl and phenethyl esters.

Examples of pharmaceutically acceptable salts are salts with inorganic bases, such as hydroxides of sodium, potassium, calcium and aluminium, or organic bases such as lysine, arginine, N-methylglucamine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di(2-ethylhexyl) - amine, piperidine, N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine,AMI. The preferred sodium and potassium salts.

As indicated above, the present invention includes in its scope also pharmaceutically acceptable bioresistance (otherwise known as proletarienne derivatives) of compounds of formula (I), i.e. compounds that have the formula, different from the above formula (I), but which, nevertheless, with the introduction of man become directly or neposredstvenno in vivo to the compound of formula (I).

Preferred compounds of formula (I) are those compounds in which each of m and n is 2; each of p and q is the number 2 and each of the groups R, which are identical, is free or C1-C6-alkyl - or phenyl-C1-C6-alkiltrimetilammony phosphonic acid group, and their pharmaceutically acceptable salts.

Examples of preferred compounds of the invention are: carbonylbis-3-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1 - methylpyrrole-2-carbonyl} (amino)naphthalene-1,5-diphosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,7 - diphosphonic acid;

carbonylbis-3-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) and the-2-carbonyl) amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,6-diphosphonic acid;

carbonylbis-3-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5,7-diphosphonic acid;

carbonylbis-2-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,5-diphosphonic acid;

carbonylbis-1-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]- 1-methylpyrrole-2-carbonyl}amino)naphthalene-5,7-diphosphonic acid;

carbonylbis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]- 1-methylpyrrole-2-carbonyl}amino)naphthalene-5,7-diphosphonic acid;

carbonylbis-1-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5,6 - diphosphonic acid;

carbonylbis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]- 1-methylpyrrole-2-carbonyl}amino)naphthalene-5,6-diphosphonic acid;

carbonylbis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]- 1-methylpyrrole-2-carbonyl}amino)naphthalene-2,5-diphosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-6,7 - diphosphonic acid;

carbonylbis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]- 1-methylpyrrole-2-carbonyl}amino)naphthalene-2,6-diphosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)acarboni}amino)naphthalene-5 - phosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-5 - phosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-6-phosphonic acid;

carbonylbis-1-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-6 - phosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-2,5,6 - triffonova acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-1,5,7 - triffonova acid;

carbonylbis-3-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene - 1,5,7-triffonova acid;

carbonylbis-3-{ [4-[(4-aminopyrrolo-1-methyl-2-carbonyl) -amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2 - carbonyl] amino)naphthalene-1,5-diphosphonic acid;

carbonylbis-4-{[4-({4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)-amino]-1-methylpyrrole-2-carbonyl} amino-1-methylpyrrole - 2-carbonyl]amino}naphthalene-1,7-diphosphonic acid;

carbonylbis-1-{ [4-({4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)-amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole - 2-carbonyl]amino}naphthalene-5,7-diphosphatase-2 - carbonyl] amino}naphthalene-5,7-diphosphonic acid;

carbonylbis-3-{[4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)-amino]-1 - methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2 - carbonyl]amino}naphthalene-1,5,7-triffonova acid; and C1-C6-alkalemia and phenyl-C1-C6-alkalemia esters and pharmaceutically acceptable salts.

Specifically preferred are methyl, ethyl and benzyl esters and sodium and potassium salts are given as examples of specific compounds of the present invention.

The compounds of formula (I) and their pharmaceutically acceptable salts will then be referred to as "compounds of the present invention" or as "active agents of the present invention".

Compounds of the invention and their salts can be obtained by a method comprising the reaction of compounds of formula II

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where n, p and R have the above values, or salt with a compound of formula (III)

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where each of the groups X, which have the same or different values, is easily removed from the group, and then, if necessary, the conversion of the compounds of formula (I) into another compound of formula (I) and/or, if necessary, the transformation of the thus obtained compounds of formula (I) into a salt, and/or, if necessary, receive free KIS the value of the formula (II) may be a salt with organic or inorganic bases, for example, the above to pharmaceutically acceptable salts of the present invention. The preferred sodium and potassium salts.

Preferred examples of the easily removable groups in accordance with the value of X are halogen atoms, in particular chlorine, or other easily replaceable group such as imidazolyl, triazolyl, p-nitrophenoxy or trichlorophenoxy.

The reaction of the compound of formula (II) or its salt with the compound of the formula (III) is similar to the well known reaction, can be performed in accordance with well known methods, for example, in accordance with the conditions described in organic chemistry for this kind of reactions, i.e., for the synthesis of urea derivatives. When in the compound of formula (III), X represents a halogen atom, for example chlorine, the reaction is preferably carried out at a molar ratio of the compounds of formula (II) or its salts and the compounds of formula (III) from about 1:0.5 to about 1:4.

In accordance with a preferred variant of the present invention, when the compound of the formula (III) is phosgene, as a source of phosgene in accordance with known methods can be applied trichloromethylcarbonate or trichloromethylcarbonate.

oto about 50oand the reaction time may vary from about 1 to about 24 hours.

The compounds of formula (I) obtained in accordance with the above methods, you can clear the usual methods, for example by chromatography on a column of silica gel or aluminum oxide and/or recrystallization from an organic solvent such as lower aliphatic alcohols or dimethylformamide or mixtures thereof, or containing water mixtures.

Similarly, the esterification or transformation into a salt of the acid of formula (I) can be known in organic chemistry methods.

The compounds of formula (II) and their salts are new compounds and are also an object of the present invention.

For example, the compound of formula (II) can be obtained by reduction of compound of formula (IV) or its salt

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where n, p and R have the above values, methods known in organic chemistry.

The compounds of formula (IV) can be obtained by reaction of the amine of formula (V) or its salt.

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where R and p have the above meanings, with a compound of formula (VI)

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where n and X have the above values.

The reaction of the amine of formula (V) or its salt with the compound of the formula (VI) is a well-known way of getting.

Alternatively, the compound of formula (IV), which is the number 2, 3 or 4, can be obtained by a multi-stage method that contains the reaction of the compound of formula (VII)

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where X has the above meanings, with an amine of formula (V) or its salt, as described above. In the reaction, which can be carried out in accordance with known techniques, obtain the connection formula (VIII) or its salt

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where R and p have the above values.

The compound of formula (VIII) or its salt to restore in accordance with known techniques, obtaining the compound of formula (IX) or its salt.

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where p and R have the above znacheniya formula (IV), where n is the number 2. If you want to obtain the compound of formula (IV) in which n is the number 3 or 4 are required under further recovery and acylation.

The compounds of formula (VI) are known compounds or they can be obtained, for example, by the methods specified in Heterocycles, vol. 27, N 8, R. 1945-52 (1988).

The compounds of formula (VII) are known products or easily determined by known methods.

The above amines of the formula (V) and their salts are new compounds and are also an object of the present invention.

Amine of formula (V) or its salt can be obtained by restoring the nitro-derivatives of the formula (X) or its salt

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where R and p have the above values, in accordance with known techniques.

Nitro-derivatives of the formula (X) can be obtained by nitration suitable free, esterified or converted into a salt of mono-, di - or triphosphates acids of naphthalene. In turn, this free, esterified or converted into a salt of the acid can be obtained by reaction of a derivative of naphthalene, substituted 1, 2 or 3 triftormetilfosfinov groups or halogen atoms, such as bromine or iodine, soutetsu>6-alkylphosphates, in the presence of organic agent main character, such as triethylamine, Diisopropylamine or pyridine, and a suitable catalytic agent, for example tetranitroaniline(O), platinum (O) or Nickel (O), at a temperature ranging from about 0oC to about 150oC.

A derivative of naphthalene, substituted 1, 2, or 3 triftormetilfosfinov groups, can be obtained by reaction of mono-, di - or trihydroxytoluene derivative of naphthalene, respectively, with a reactive derivative triftoratsetata, for example an acid chloride or anhydride, in the presence of organic agent main character, such as pyridine or triethylamine, in the case of carrying out the reaction in an organic inert solvent, for example methylene chloride, diethyl ether or toluene.

Salts of compounds of formula (IV), (V), (VIII), (IX) or (X) may be salts with organic or inorganic bases, for example the grounds specified above for compounds of formula (I), preferably the sodium and potassium salts.

Pharmacology

New naftalinovui acid of the formula (I) and their pharmaceutically acceptable salts in accordance with the Rus human immunodeficiency (HIV).

It is found that, for example, typical compounds of the invention, carbonylbis-3-({4-[(4-aminopyrrolo-1-methyl - 2-carbonyl)amino]-1-methylpyrrole-2-carbonyl} amino)-naphthalene-1,5-diphosphonic acid and carbonylbis-4-({4-[(4-aminopyrrolo-1-methyl - 2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)-naphthalene-1,7 - diphosphonic acid, active in the biological test described in I. Natl. Cancer Inst., 81, 557-586 (1989).

The person suffering from lentiviruses infection, thus can be treated by the method of introducing him an effective amount of one of the compounds of the present invention. Thus, the compounds of the invention can be used to treat infectious diseases caused by lentiviruses, in particular a human immunodeficiency virus, particularly HIV-1 or HIV-2.

Compounds of the present invention can also be applied to obtain a medicinal drug used in the treatment of a person suffering from lentiviruses infectious disease. This product can be used as antiuniverse tools, such as anti-HIV-1 or anti-HIV-2 funds. This drug can also be used to alleviate the symptoms induced lentiviruses human diseases, stradajuwih in order to apply for funds which is used in the treatment of a person who is seropositive disease, stress or pathology caused by infection with lentiviruses, in particular by Vica, or which is suffering from such induced disease, such as, for example, the syndrome lympadenopathy (LS), the disease caused by associated with AIDS complex (ARC) or AIDS or Kaposi sarcoma. The patient can, therefore, facilitate or improve.

In these therapeutic applications, the compounds of the invention can be entered in the usual way, for example parenteral, for example intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally, preferably intravenous injection or infusion. The dosage depends on age, weight and condition of the patient and the route of administration of the compounds. Suitable dose of the compounds of the invention, such as carbonylbis-3-({4-[(4- aminopyrrolo-1-methyl-2-carbonyl)amino] -1-methylpyrrole-2-carbonyl} amino)-naphthalene-1,5-diphosphonic acid or its pharmaceutically acceptable salts, with the introduction of adults ranges from about 0.5 to about 300 mg with the introduction of 1-4 times a day.

Compounds of the invention can be used in the method of treating the above-mentioned pathological conditions,ormula (I) or its pharmaceutically acceptable salt, and pharmaceutical compositions containing other pharmaceutically active funds. The present invention also provides products containing a compound of the formula (I) or its pharmaceutically acceptable salt and a second pharmaceutically active agent, as a combined preparation for separate, simultaneous or sequential use in the treatment of a person suffering from lentiviruses infectious disease, in particular, caused by Vica. The second active agent is typically a medicine that affects the pathogenesis of HIV-induced disease.

Compounds of the present invention can be applied,for example, with different active means, in particular those that affect reverse transcriptase, antimicrobial and antitumor means or mixtures of two or more such means. Interest drugs include nucleoside reverse transcriptase inhibitors, for example Neverlin; derivatives of nucleosides, such as zidovudine and didanosine; acyclovir; ribavirin; ascorbic acid; protease inhibitors; cytokines, such as 1L-1, 1L-2, 1L-3 or 1L-4; growth factors; interferons such as alpha - or Itin, methoxypropionitrile, idarubitsin, etoposide, fluorouracil, melphalan, cyclophosphamide, bleomycin, vinblastine and mitomycin; immunomodulatory funds, in particular, Immunostimulants, gamma-globulins, immunoglobulins and monoclonal antibodies, antibiotics and antimicrobial products.

Typical antibacterial agents may include penicillin in combination with an aminoglycoside (e.g. gentamicin or tobramycin).

However, you can apply some well-known additional tools, such as cephalosporin.

Dose the introduction of these drugs will vary depending on the condition of the patient. Regimen medicines should therefore be adjusted, in particular, to the condition of the patient's susceptibility and associated methods of treatment that are common to any therapy, it may need to be adjusted in accordance with changes in the patient's condition and/or in light of other clinical conditions.

The pharmaceutical composition used in the invention may contain the compound of formula (I) or its pharmaceutically acceptable salt as an active substance in combination with one or several the t standard methods, they are administered in pharmaceutically acceptable form. For example, the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of a sterile aqueous isotonic salt solutions. The suspensions or solutions for intramuscular injections may contain, together with the active compound in pharmaceutically acceptable carrier, e.g. sterile water, olive oil, etiloleat, glycols, such as propylene glycol, and, optionally, a suitable amount hydrochloride lidocaine.

In the form for local application, such as creams, lotions or pastes for use in dermatological treatment, the active ingredient can be mixed with conventional oil or emulsifying fillers.

Solid oral forms such as tablets and capsules, may contain together with the active compound of the diluents, for example lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium stearate or calcium and/or polyethylene glycols; binding agents, e.g. starches, Arabic gum, gelatin, Medicago acid, alginates, sodium salt glycolate, starch, foaming mixtures; dyestuffs; sweeteners; wetting means; for example lecithin, Polysorbate, dodecylsulfate; and, in General, non-toxic and pharmacologically inactive substances used in pharmaceutical finished formulation. These pharmaceutical drugs can do in a known manner, for example by means of mixing, granulating, tabletting, education sheath of sugar or film.

The following examples illustrate but do not limit the present invention.

Example 1

Actuarialy ether carbonylbis-3-({ 4-[(4-aminopyrrolo-1 - methyl-2-carbonyl)amino] -1-methylpyrrole-2-carbonyl} amino)- naphthalene-1,5-diphosphonic acid.

In ice, the solution of tetraethyl-3-[1-methyl-2 - errorcorrected-4-(1-methyl-4-amino-2-errorcorrected)] naphthalene-1,5-diphosphonate (to 4.23 g, between 6.08 mmole, as hydrochloride) and triethylamine (3.5 ml, 25 mmole) in methylene chloride (100 ml, contains no ethanol) was added dropwise with stirring a solution of trichloromethylcarbonate (325 mg, 1.09 mmole) in methylene chloride (10 ml). After incubation for 3 h at room temperature, the entire reaction mixture is ewenny the residue was purified flash-chromatography on silica gel 60 (CH2Cl2-CH3OH, 90:10).

The solid residue was transferred into ethyl acetate, filtered and dried, obtaining the title compound (3.11 g, so pl. 195-205oC) in the form of solid microcrystalline pale brown substance.

1H NMR spectrum (200 MHz, DMSO-d6):10,45, 9,88 (two singlets, 2H), 9,23 (d, 1H, j=1.1 Hz), 8,7-or 8.5 (m, 2H), 8,17 (s, 1H), 8,12 (DDD, 1H, j=1.1 Hz, j= 7,2 Hz, I= to 15.8 Hz), 7,63 (DDD, 1H, j=3,7 Hz, j=7,2 Hz, 08,6 Hz), 7,35, 7,27 (two doublet, 2H, j=1,8 Hz), 7.03 is, 6,84 (two doublet, 2H, j=1,8 Hz), 4.2 3.9 (m, 8H), 3,84, 3,89 (two singlets, 6H), 1,3-1,1 (m, 12H).

Mass spectrum (-) FAB: (M-H)=1344.

Example 2

Actuarialy ether carbonylbis-4-({4-[(4-aminopyrrolo-1 - methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)- naphthalene-1,7-diphosphonic acid.

The method described in example 1, using 780 mg of the hydrochloride tetraethyl-4-[1-methyl-2-errorcorrected-4-(1-methyl - 4-amino-2-errorcorrected)]-naphthalene-1,7 - diphosphonate as starting compound was obtained the title compound as an orange solid (270 mg, 36%).

1H NMR spectrum (200 MHz, DMSO-d6): 9.91, 10,30 (two singlets, 2H), to 8.94 (d, 1H, I=to 15.8 Hz), of 8.0 to 8.3 (m, 3H), 7,7-8,0 (m, 2H), 3,32, 7,37 (two doublet, 2H, j=11.8 Hz), 6,84, 7,03 (two doublet, 2H, j=1,8 Hz), 3,9-4,2 (m, 8H), 3,85, 3,84 (two singlets, 6H), of 1.1 - 1.3 (m, 12H).

Example 3

Carbonylbis-3-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl} amino)naphthalene-1,5 - diphosphonic acid and its Terentieva salt

In ice RA is Yali solution bromotrimethylsilane (10 ml) in CH3CN (10 ml). After conditioning for 24 hours at room temperature under reduced pressure evaporated volatile organic components. The residue was transferred into acetone and was added water (500 mg), diluted (CH3)2CO (10 ml). After stirring for 4 h formed microcrystalline portion was separated by filtration, washed with acetone, methanol, simple ether and dried in vacuum, obtaining the title compound (779 mg).

Elemental analysis:

C45H44N10O17P4< / BR>
The expect., %: C 48,22, H 3.96 POINTS, N 12,50, O 24,27, P 11,05

Found, %: C 44,46, H 4.26 deaths, N 11,18, P 9,48

1H NMR spectrum (200 MHz, DMSO-d6, T=50oC): 9,74, 10,23 (two singlets, 2H), 9,07 (s, 1H), 8,72 (d, 1H, j=8.5 Hz), of 8.47 (DD, 1H, j= 1.9 Hz, I=16,9 Hz), with 8.05 (DD, 1H, j=7,1 Hz, j=15.6 Hz), 8,01 (s, 1H), of 7.48 (DDD, 1H, j=3.2 Hz, I= 7,l Hz, j=8,5 Hz), 6,83, 7,00, 7,25, 7,31 (four doublet, 4H, I=1,8 Hz), 3,85, 3,89 (two singlets, 6H).

Thus obtained acid (650 mg, of 0.58 mmole) was dissolved in water (50 ml) and neutralized NaHCO3(195 mg, 2,32 mmole) to a pH of 6.5-7.

The solution was filtered, concentrated under reduced pressure to a small volume and was dried by freezing, getting microcrystalline pale brown salt.

Elemental analysis;

C45H40CLASS="ptx2">

1H NMR spectrum (200 MHz, D2O + NaOD): 8,76 (m, 2H), 8,02 (m,2H), 7,47 (m, 1H), 6,61, 6,84, 6,99, 7,22 (four doublet, 4H, I=1,9 Hz), 3,76, 3,84 (two singlets, 6H).

Example 4

Carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino] -1-methylpyrrole-2-carbonyl} amino) naphthalene-1,7-diphosphonic acid and its Terentieva salt

The method described in example 3, using 197 mg octachloro ether carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl} amino)-naphthalene-1,7 - diphosphonic acid as starting compound was obtained the title compound as an orange solid (160 mg, 98%).

1H NMR spectrum (200 MHz, DMSO-d6, T = 50oC): 9,78, of 10.05 (Two singlets, 2H), 9,13 (d, 1H, j = 15.6 Hz), 8,0-8,2 (m, 3H), of 7.6 to 7.9 (m, 2H,), 6,85, 7,01, 7,29, 7,33 ( four doublet, 4H, I=1,8 Hz), 3,85, 3,86 (two singlets, 6H).

Neutralization of acid NaHCO3received the title TETRANITRATE salt as a pale brown solid (163 mg, 98%).

1H NMR spectrum (200 MHz, D2O + NaOD, T=50oC): 9,04 (d, 1H, j= 14 Hz), 8,03 (DD, 1H, j= 7,4 Hz, I= of 13.7 Hz), 7,7-8,0 (m, 2H), 7,34 (DD, 1H, j= 2.3 Hz, j= 7,4 Hz), 6,78, 6,99 (two singlets, 2H),3,80, 3,85 (two singlets, 6H).

Elemental analysis:

C45H40N10Na4O17Pthe e connection in the form of their free acids and sodium salts:

carbonylbis-3-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-1,6-diphosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-1,6 - diphosphonic acid;

the carbonyl-3-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino] -1 - methylpyrrole-2-carbonyl}amino)naphthalene-5,7-diphosphonic acid;

carbonylbis-2-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino] - 1-methylpyrrole-2-carbonyl}amino)naphthalene-1,5-diphosphonic acid;

carbonylbis-1-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-5,7 - diphosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-5,7-diphosphonic acid;

carbonylbis-1- ({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5,6 - diphosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-5,6-diphosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-2,5 - diphosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl} amino] -1-methyl is Ino]-1-methylpyrrole-2 - carbonyl}amino)naphthalene-2,6-diphosphonic acid;

carbonylbis-4- ({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-2,7-diphosphonic acid;

carbonylbis-1-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-5-phosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-5 - phosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl - 2-carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-6 - phosphonic acid;

carbonylbis-1-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-6-phosphonic acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-2,5,6 - triphosphonate acid;

carbonylbis-4-({ 4-[(4-aminopyrrolo-1-methyl-2 - carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)naphthalene-1,5,7 - triphosphonate acid and

carbonylbis-3- ({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl) amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene - 1,5,7-triphosphonate acid.

Example 5

Hydrochloride tetraethyl-3-[1-methyl-2-errorcorrected-4-(1 - methyl-4-amino-2-errorcorrected)]naphthalene-1,5-diphosphate

Tetraethyl-3-[1-methyl-2-errorcorrected-4-(1-methyl-4 - nitro-2-errorcorrection 5% Pd/C (500 mg) in a Parr apparatus until the termination of absorption of H2. After separation of the catalyst, the methanol evaporated under reduced pressure. The residue was transferred into diethyl ether, separated microcrystalline solid product was filtered, washed and dried at 60oC under reduced pressure, obtaining the title compound (4,43 g, 96%) as hydrochloride.

Elemental analysis:

C30H40ClN5O8P2found (calculated), %: C 49,93 (51,76), H 5,93 (5,79), Cl 5,00 (5,09), N BEING 9.61 (10,06)

Mass spectrum (-) FAB: (M-H) = 658.

1H NMR spectrum (400 MHz): 10,13, 10,46 (two singlets, 2H), 9,85 (W, s, 3H), 9,23 (s, 1H), at 8.60 (d, lH, j= 8.5 Hz), 8,56 (DD, 1H, j = 2.0 Hz, j= 17.3 Hz) to 8.12 (DD, 1H, j = 7,3 Hz, j = 17.0 Hz), to 7.64 (DDD, 1H, j = 3.5 Hz, j= 7,3 Hz, I= 8.5 Hz), 7,26, was 7.36 (two doublet, 2H, j= 1,8 Hz), 7,00, 7,10 (two doublet, 2H, 7 = 2.0 Hz), 4,00-4,2 (m, 8H), to 3.89 (s, 6H), 1,2-1,3 (m, 12 H).

Example 6

Hydrochloride tetraethyl-4-[1-methyl-2-errorcorrected-4- (1-methyl-4-amino-2-errorcorrected)]naphthalene-1,7 - diphosphonate

The method described in example 5 using 1.0 g of tetraethyl-4-[1-methyl-2-errorcorrected-4-(1-methyl-4-nitro-2 - errorcorrected)]naphthalene-1,7-diphosphonate as starting compound was obtained the title product as a brown solid (0.95 g, 94%).

1H NMR spectrum (80 MHz, DMSO-d6): 10,3 (s, 1H), 10,15 (

Tetraethyl-3-[1-methyl-2-errorcorrected-4-(1-methyl-4 - nitro-2-errorcorrected)]naphthalene-1,5-dmosfet

In a mixture of tetraethyl-3-(1-methyl-4-amino-2 - errorcorrected)naphthalene-1,5-diphosphonate (7,3 mole) in the form of hydrochloride, and triethylamine (3.5 ml, 25 mmole) in CH2Cl2(100 ml, contains no ethanol) under cooling with ice bath, was added dropwise the acid chloride of 1-methyl-4-nitro-2-terracarbon acid (1,41 g, 7.5 mmole) in 15 ml of CH2Cl2. After keeping the mixture for 1 hour in ice and 1 hour at room temperature, the organic phase is washed with acid and the solution (NaHCO3) dried (Na2O4) and evaporated under reduced pressure. The crude residue is again dissolved in ethanol (20 ml), was treated to induce crystal formation. Crystallization was completed by the addition of diethyl ether (20 ml) and the formed solid crystalline yellow product was separated by filtration, washed with a mixture of ethanol and diethyl ether (1: 1) and Spili at 50oC under reduced pressure, obtaining the title compound (4,50 g, so pl. 163 - 168oC, yield 89%).

Elemental analysis:

C30H37N5O10P2Found (calculated), O: P 9,85 (10,16)

Mass spectrum (-) FAB: (M-H) = 688.

Example 8

Tetraethyl-4-[1-methyl-2-errorcorrected-4-(1-methyl-4 - nitro-2-errorcorrected)]naphthalene-1,7-diphosphonate

The method described in example 7, with the use of 1.84 g of the hydrochloride tetraethyl-4-(1-methyl-4-amino-2 - errorcorrected)naphthalene-1,7-diphosphonate as connection received 1.89 g of the title compound (yield 85%).

1H NMR spectrum (200 MHz, DMSO-d6): 10,34, 10,37 (two singlets, 2H), to 8.94 (d, 1H, j = 16.0 Hz), 8,1-8,3 (m, 2H), 7,7-7,9 (m, 2H), 7.62mm, 8,20 (two doublet, 2H, j=2.1 Hz), 7,32, 7,40 (two doublet, 2H, j=1.9 Hz), 3,9-4,2 (m, 8H), 3,86, 3,97 (two singlets, 6H), of 1.1-1.3 (m, 12H).

Mass spectrum (-)FAB (M-H) = 688

Example 9

Tetraethyl-3-(1-methyl-4-amino-2-errorcorrected)naphthalene - 1,5-diphosphate

Tetraethyl-3-(1-methyl-4-nitro-2-errorcorrected)-naphthalene - 1,5-diphosphonate (4.15 g, 7,31 mmole) dissolved in methanol (150 ml) and 1 N HCl (7.5 ml) was first made in the presence of 5% Pd/C in a Parr apparatus until cessation of hydrogen absorption. After separation of the catalyst by filtration with the use of the accelerator by filtration, the methanol is evaporated under reduced pressure and the residue was dried in to 9.6 (s, 1H), 9,05 (m, 1H), 8,67 (DD, 1H, j= 1.9 Hz,j= 17.6 Hz), 8,67 (d, 1H, j= 8.6 Hz), to 8.12 (DD, 1H, j= 6,5 Hz, I= 15,9 Hz), of 7.75 (s, 1H), (m, 1H), 6.87 in (s, 1H), 3.9 to 4.4 (m, 8H), of 3.75 (s, 3H), 1,0-1,4 (m, 12 H).

Example 10

Hydrochloride tetraethyl-4-(1-methyl-4-amino-2 - errorcorrected)naphthalene-1,7-diphosphonate

The method described in example 9, using 1,89 g tetraethyl-4-(1-methyl-4-nitro-errorcorrected)naphthalene - 1,7-diphosphonate as starting compound was obtained 1.84 g of the title compound as a brown solid (yield 96%).

1H NMR spectrum (80 MHz, DMSO-d6): 10,45 (s, 1H), 10,2 (W., 3H), of 8.95 (d, 1H), 7,65 an 8.4 (m, 4H), 7,2-7,35 (m, 2H), 3,8-4,4 (m, 11H), 1.1 to 1.4 (m, 12H).

Example 11

Tetraethyl-3-(1-methyl-4-nitro-2-errorcorrected)naphthalene - 1,5-diphosphate

In ice, the solution of the hydrochloride hemihydrate tetraethyl-3-aminonaphthalene-1,5-diphosphonate (3.75 mg, 8,14 mmole) and triethylamine (3.75 ml, 27 mmole) in CH2Cl2(60 ml, contains no ethanol) was added dropwise to the acid chloride of 1-methyl-4-nitro-2 - terracarbon acid (1.89 g, 10 mmole) in 15 ml of CH2Cl2.

After incubation for 4 hours at room temperature the organic phase is washed with water, 1 N HCl, 5% solution of NaHCO3, dried (Na2O4) and evaporated under reduced pressure dody the residue was transferred into diethyl ether, was filtered and dried, obtaining the title compound (4,17 g, so pl. 250,5-252,5oWith the release of 90%).

Elemental analysis:

C24H31N3O9P2found (calculated), %: C 50,87 (50,79), H of 5.53 (5,51), N 7,35 (7,40).

1H NMR spectrum (80 MHz, CDCl3): 9,77 (s, 1H), 9,23 (d, 1H, j=2.2 Hz), 8,65 (DD, 1H, j=1.4 Hz, j= 8,4 Hz), 8,55 (DD, 1H, j= 2.2 Hz, I= 17,4 Hz), 8,13 (DDD, 1H, j= 1.4 Hz, j= 7,3 Hz, j= 16.0 Hz), and 7.3 to 7.7 (m, 3H), 3.9 to 4.5 (m, 8H), a 3.87 (s, 3H), 1,1-1,6 (m, 12H).

Mass spectrum E1 (M)+= 567.

Example 12

Tetraethyl-4- (1-methyl-4-nitro-2-errorcorrected) naphthalene - 1,7-diphosphonate

The method described in example 11, using 2.0 g of the hydrochloride tetraethyl-4-aminonaphthalene-1,7-diphosphonate as starting compound was obtained 2,63 g of the crude title compound, which was recrystallize from benzene to highlight 1,90 g microcrystalline white solid product (so pl. 204 - 205oC, 76%).

1H NMR spectrum (200 MHz, CDCl3): of 9.89 (s, 1H), cent to 8.85 (DD, 1H, j=1.5 Hz, I= 15,9 Hz), of 7.9 to 8.1 (m, 2H), 7,79 (DD, 1H, j = 3,4 Hz,j=7.9 Hz), to 7.67, 8,05 (two doublet, 2H, j= 1,8 Hz), 7,52 (DDD, 1H, j=1.5 Hz, j= 8.7 Hz, j=11,6 Hz), 4,0-4,3 (m, 8H), Android 4.04 (s, 3H), 1,2-1,4 (m, 12H).

Mass spectrum E1 (M)+= 567.

Example 13

Tetraethyl-3-aminonaphthalene-1,5-diphosphate

Tetraethyl-3-NIT is I H2in the presence of 5% Pd/C in a Parr apparatus until the termination of absorption of H2. After separation of the catalyst by filtration application accelerator filtering the methanol evaporated under reduced pressure. The residue was stirred with ethanol (10 ml) and diethyl ether (50 ml) and the formed crystalline solid product was separated by filtration, washed and dried, obtaining the title product, isolated as the hydrochloride hemihydrate (of 3.78 g, decomposes at 230-240oC, yield 91%).

Elemental analysis:

C18H28ClN6P2H2O found (calculated), %: C 46,99 (46,91), H 6,32 (6,34), N 3,02 (3.04 from).

1H NMR spectrum (80 MHz, CDCl3): 8,3 (W, s, 3H), 9,03 (d, 1H, j= 2.1 Hz), 8,77 (d, 1H, j= 8,5 Hz) and 8.50 (DD, 1H, j= 2.1 Hz, j= 16.6 Hz), compared to 8.26 (DDD, 1H, j= 1.3 Hz, j= 7,2 Hz, j = 15.6 Hz), the 7.65 (DDD, 1H, j=3,9 Hz, j = 7,2 Hz, j=8.5 Hz), 3.9 to 4.5 (m, 8H), 1.3 to 1.5 (m, 12H).

Example 14

Hydrochloride tetraethyl-4-aminonaphthalene-1,7-diphosphonate

The method described in example 13, using 2.7 g tetraethyl-4-nitronaphthalene-1,7-diphosphonate was obtained 2.6 g of the title product as a pale yellow solid (yield 94%).

1H NMR spectrum (80 MHz, CDCl3+ D2O): 8,9 ( s, 1H), 8,1 (DD, 1H), 7,65-to 7.95 (m, 2H), 6,85 (DD, 1H), 3,9-4,4 (m, 8H), 1.2 to 1.5 (m, 12H).

When varali in ice 96% H2SO4and dropwise to the solution was added sulfonium mixture (2.5 ml, 90% HNO37.5 ml of 96% H2SO4within 15 minutes

After keeping under ice cooling, the reaction mixture was poured into a mixture of ice and water and the mixture was extracted with ethyl acetate. The organic extract was washed with water, a solution of NaHCO3was dried, concentrated under reduced pressure to 20 ml and diluted with 30 ml of cyclohexane. After cooling, ice formed crystalline solid product was separated by filtration, washed and dried, obtaining the title compound (8,48 g, so pl. 117-118,5oC, 74.7 per cent).

Elemental analysis:

C18H25NO8P2found (calculated), %: C 48,31 (48,54), H 5,64 (5,66), N 2,98 (3,14).

1H NMR spectrum (80 MHz, CDCl3): 9,75 (DD, 1H, j= 2.3 Hz, j=1.0 Hz), 8,97(DD, 1H, j= 2.3 Hz, j= 16.6 Hz), 8,93 (m, 1H), 8,46 (DDD, 1H, j= 1.3 Hz, j= 7,1 Hz, I= 15,9 Hz), the 7.85 (DDD, 1H, j = 3.6 Hz, j= 7,1 Hz, j= 8,4 Hz), 3,9-4,6 (m, 8H), to 1.38 (t, 12H, j= 7.2 Hz). Mass spectrum E1 (M)+= 445.

Example 16

Tetraethyl-4-nitronaphthalene-1,7-diphosphonate

1,7-Dateformat.short-4-nitronaphthalene (266 mg, 0.57 mmole), diethylphosphate (315 mg, 2,28 mmole) and triethylamine (345 mg, of 3.42 mmole) was dissolved in 20 ml of CH3CN in the atmosphere N2.

C od is Tim refrigerator within 2 hours.

After cooling, the solvent was removed under reduced pressure and the residue was again dissolved in ethyl acetate, washed with water, diluted hydrochloric acid, a solution of NaHCO3, dried and evaporated in vacuum. After purification column chromatography (silicon dioxide as eluent was used a mixture of ethyl acetate/methanol 96: 4) was obtained the title product as a yellow solid (198 mg, so pl. 54 - 57oC, yield 78%).

1H NMR spectrum (80 MHz, CDCl3) to 9.15 (DD, 1H), 7,9 and 8.6 (m, 4H), 4.0 to 4.5 (m, 8H), 1,1-1,5 (m, 12H).

Example 17

Tetramethylnaphthalene-1,5-diphosphate

Naphthalene-1,5-dateformat.short (16,46 g, 40 mmole) (obtained by treating 1,5-dihydroxynaphthalene anhydride triftormetilfosfinov in pyridine, T. pl. 112-113oC), diethylphosphate (13,81 g, 100 mmole), dry N,N-diisopropylethylamine (15,51 g, 120 mmole), tetrakis(triphenylphosphine) palladium (O) (1,00 g 0,86 mmole) in 50 ml of dry N,N-dimethylformamide was heated at 95-100oC for 3 hours. After cooling, the reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water, diluted acid solution of NaHCO3were dried (NaSO4), concentrated under reduced pressure to 50 ml and diluted to 25 Manie, washed with diethyl ether and dried, obtaining the title product (12,23 g, so pl. 169-171oC, the yield of 76.4%).

Elemental analysis:

C18H26O6P2found (expect.), %: C 53,74 (54,00), H 6,53 (6,55).

Mass spectrum E1 (M)+= 400.

1H NMR spectrum (80 MHz, CDCl3): 8,82 (DD, 2H, j=8.7 Hz, j= 1.2 Hz), 8,30 (DDD, 2H, j=1.2 Hz, j= 6,9 Hz, j=15.6 Hz), the 7.65 (DDD, 2H, j= 3,9 Hz, j= 6,9 Hz, j=8.7 Hz), 3.9 to 4.5 (m, 8H), 1,32 (t, 12H, j=7.2 Hz).

Example 18

1,7-Dateformat.short-4-nitronaphthalene

Naphthalene-1,7-dateformat.short (2,12 g, 5 mmol) (obtained by the processing of 1.7 dihydroxynaphthalene anhydride of triftoratsetata in pyridine) was added in small portions 90% nitric acid (12.5 ml), cooled to -10oC (bath with a mixture of ice and salt).

The resulting reaction mixture was stirred 30 min and then was poured into 100 g of a mixture of ice/water and was extracted with diethyl ether.

The organic extract was washed with water, a solution of NaHCO3, water and dried.

The solvent was removed under reduced pressure and the residue was purified flash-chromatography (silicon dioxide). By elution with a mixture of cyclohexane/ethyl acetate (90: 10) provided the title product as a pale yellow solid Krista Hz), of 8.1 (d, 1H, j= 2,8 Hz), 7,65 is 7.85 (m, 2H).

Example 19

Actuarialy ether carbonylbis-3-({ 4-[(4-aminopyrrolo-1-methyl - 2-carbonyl)amino] -1-methylpyrrole-2-carbonyl}amino)-1 - methylpyrrole-2-carbonyl]amino} naphthalene-1,5-diphosphonic acid.

Tetraethyl-3-[1-methyl-2-errorcorrected-4-(1-methyl-4 - amino-2-errorcorrected)naphthalene-1,5-diphosphonate as hydrochloride (920 mg, 1,32 mmole), dissolved in dimethylformamide, and 4,4'-carbonylbis-[2-(N-imidazolidinyl)-4-amino-1 - methylpyrrole] (250 mg, of 0.62 mmole) was heated for 3 hours at 50 - 70oC to dissolve the derivative of imidazole. The dimethylformamide is evaporated under reduced pressure, the residue was dissolved in CH2Cl2and washed with water, 0.5 N HCl, 5% solution of NaHCO3saturated NaCl solution, dried Na2SO4and evaporated under reduced pressure.

The crude residue was purified flash-chromatography on silica gel, elwira a mixture of CH2Cl2/ethanol 85:15). Received the title compound as a pale brown crystalline solid substance (710 mg, yield 68%).

1H NMR spectrum (200 MHz, 10,46, 10,00, 9,83 (three singlets, 3H), 9,24 (s, 1H), 8,7-or 8.5 (m, 2H), 8,21 (s, 1H), 8,12 (DDD, 1H,I= 1,2, j=7,1 Hz, I= 16,8 Hz), to 7.64 (DDD, 1H, j= 3 Hz, j= 8.7 Hz), 7,35, 7,28, 7,24, 7,08, 7,02, 6,81 (six doublets, 6R 20

Actuarialy ether carbonylbis-4-{(4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino] -1-methylpyrrole-2-carbonyl} amino)-1 - methylpyrrole-2-carbonyl] amino}naphthalene-1,7-diphosphonic acid.

Hydrochloride tetraethyl-4-[1-methyl-2-errorcorrected-4- (1-methyl-4-amino-errorcorrected)] naphthalene-1,7-diphosphonate (172 mg, 2,48 mmole) and 4,4'-carbonylbis-[2-(N - imidazolidinyl)-4-amino-1-methylpyrrole] (503 mg, 1,24 mmole) suspended in dry dimethylformamide (30 ml) and the suspension was stirred at 70oC for 2.5 hours. The solvent is evaporated under reduced pressure and the residue was chromatographically on a column of silica gel with elution with a mixture of methylene chloride/ethanol (4:1) to give the title compound as a pale yellow solid product (600 mg).

1H NMR spectrum (80 MHz, DMSO-d6): a 1.25 (m, 12H, 4-CH2CH3), 3,7-4,3 (m, 17H, 4-CH2CH3+ 3-CH3), 6,8, 7,0, 7,1, 7,2 (four doublet, 4H, pyrrole), 7,35 (s, 2H, pyrrole), of 7.6 to 8.4 (m, 5H, 2+3+5+6+NHCO ureido), of 8.95 (d, 1H, 8), 9,8,10,0, of 10.25 (three singlets, 3H, 3-CONH).

Mass spectrum (-) FAB (M-H) = 1588.

Similarly, you can obtain the following compounds in the form of free acid and sodium salt:

carbonylbis-1-{ [4-({4-[(4- aminopyrrolo-1-methyl-2-carbonyl)-amino]-1-methylpyrrole-2-Kerberos-1-methyl-2 - carbonyl)-amino]-1-methylpyrrole-2-carbonyl}amino]-1 - methylpyrrole-2-carbonyl]amino}naphthalene-5,7-diphosphonic acid and

carbonylbis-3-{ (4-{ [4-[{(4-aminopyrrolo-1-methyl-2-carbonyl)-amino]- 1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2-carbonyl] amino} naphthalene-1,5,7-triphosphonate acid;

Example 21

Carbonylbis-3-{ [4-({ 4-[{(4-aminopyrrolo-1-methyl-2 - carbonyl)-amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole - 2-carbonyl] amino} naphthalene-1,5-diphosphonic acid and its Terentieva salt

Actuarialy ester obtained in example 19 (620 mg, of 0.39 mmole) in CH2Cl2(50 ml, contains no ethanol) were treated with bromotrimethylsilane (3.9 ml, 30 mmole) as described in example 3. After processing the reaction mixture was awarded the title acid as a pale brown crystalline product (540 mg).

1H NMR spectrum (200 MHz, DMSO-d6): 10,32, 9,98 (three singlets, 3H), remaining 9.08 (s, 1H), 8,68 (d, 1H, I= 8,9 Hz), 8,48 (DD, 1H, j= 2.2 Hz, I= 17,1 Hz), 8,1 (sh. s, 1H), 8,04 (DDD, 1H, j=1.3 Hz, j = 7,1 Hz, I= 15,8 Hz), 7,50, 7,26, 7,24, 7,06, 7,01, 6,81 (six doublets, 6H, j= 1.7 Hz), 3,88, 3,86, 3,83 (three singlets, 9H).

Mass spectrum (-) FAB (M-H) = 1363.

Thus obtained acid (520 mg) was dissolved in water (50 ml) and neutralized with 0.5 N NaOH to pH 6.0. The solution was filtered, concentrated to small volume under reduced pressure and dried by freezing, getting microcrystalline pale brown Sol.: C 39,08 (47,11), H 5,11 (3,61), N 11,08 (13,50), loss during drying of 16.00%.

1H NMR spectrum (400 MHz, DMSO-d6): same as the free acid

Mass spectrum (-) FAB (M-H) = 1451 (M-Na) = 1429.

Example 22

Carbonylbis-4-{[4-({4-[{(4-amino-1-methylpyrrole-2-carbonyl)- amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2 - carbonyl]amino}naphthalene-1,7-diphosphonic acid and its Terentieva salt

Actuarialy ether carbonylbis-4-{ [4-({ 4-[(4-amino-1 - methylpyrrole-2-carbonyl)amino] -1-methylpyrrole-2-carbonyl} amino) -1-methylpyrrole-2-carbonyl] amino} naphthalene-1,7-diphosphonic acid (578 mg, 0,364 mmole) was dissolved in dry methylene chloride (75 ml) and with stirring in a nitrogen atmosphere at 0oC was added dropwise bromotrimethylsilane (4,54 mg, 35 mmole). The whole mixture was stirred at 0oC for 1 hour and then at room temperature for 66 hours. The solvent is evaporated, the residue is suspended in acetone (100 ml) and treated with a mixture of water/acetone (1:5) (6 ml). The suspension was stirred at room temperature for 3 hours and then filtered, obtaining the title product in the form of the free acid (490 mg, brown solid).

1H NMR spectrum (80 MHz, DMSO-d6): 3,7-4,0 (m, 9H, 3-CH3), 6,8 7,0, 7,1, 7,2 (four doublet, 4H, pyrrole), 7,35 (m, 2H, Pirro"ptx2">

Thus obtained acid (480 mg, 0,352 mmole) was dissolved in water (20 ml) and was neutralized with sodium bicarbonate (118 mg, 1,406 mmole). A solution of Terentieva salt was filtered and dried by freezing, receiving the title compound in the form of a soft solid (515 mg).

1H NMR spectrum (400 MHz, DMSO-d6+ CF3COOH): 3,84, 3,86, a 3.87 (three singlets, N, 3-NCH3), 6,81, 7,03, 7,10, 7,24, 7,32, 7,37 (six doublets, j= 1.7 Hz, 6H, pyrrole), 7,72 (DD, j = 2.4 Hz, j=7.9 Hz, 1H, 3), to 7.77 (m, 1H, 6), 8,10 (m, 2H, 5+2), 8,3 (W, s, 1H, NHCO ureido), 9,10 (d, I=15,4, 1H, 8), 9,85, 10,02, 10,19 (three singlet, 3H, 3-CONH).

Mass spectrum (-) FAB (M+H+2Na) = 1407.

Similarly, you can obtain the following compounds in the form of free acid and sodium salt:

carbonylbis-1-{[4-({4-[{(4- aminopyrrolo-1-methyl-2-carbonyl)-amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2-carbonyl]amino}-naphthalene-5,7 - diphosphonic acid;

carbonylbis-4-{ [4-({ 4-[(4-aminopyrrolo - 1-methyl-2-carbonyl)-amino]-1-methylpyrrole-2-carbonyl} amino)-1 - methylpyrrole-2-carbonyl] amino} naphthalene-5,7-diphosphonic acid and

carbonylbis-3-{[4-({4-[{(4-aminopyrrolo-1-methyl-2-carbonyl)- amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2 - carbonyl] amino} naphthalene-1,5,7-triphosphonate acid.

Example 23

4,4'-Carbol].

To a solution of 4-amino-1-methylpyrrole-2-carboxylic acid (4,00 g, and 22.6 mmole, as hydrochloride), sodium bicarbonate (7,56 g, 90 mmole) in water (75 ml) and 1,4-dioxane (25 ml) was added dropwise a solution of bis (trichloromethyl) carbonate (1.25 g, 4.2 mmole) in 1,4 - dioxane (10 ml) under stirring and ice cooling. The reaction mixture was acidified to pH 1-2 with diluted hydrochloric acid, the precipitated white product was separated by filtration, washed with water and dried, obtaining the title acid (to 3.89 g, yield 95%).

1H NMR spectrum (DMSO-d6) 12,1 (W., 1H, exchanges with D2O), and 8.2 (s, 1H, exchanges with D2O ), 7,12 (d, 1H), 6,62 (d, 1H), 3,80 (s, 3H).

In the solution of the above acid (3,29 g, 10,75 mmole) in dimethylformamide (50 ml) in portions under stirring at room temperature was added N, N'-carbonyldiimidazole (5,80 g, a 32.6 mmole). After 4 hours, the precipitated solid product was separated by filtration, washed with dimethylformamide, diethyl ether, and dried, obtaining the title compound (3,90 g, yield 90%).

1H NMR spectrum (DMSO-d6): 8,75 (W., s, 1H), 8,25 (m, 1H), of 7.70 (t, 1H), 7,52 (d, 1H), 7,13 (m, 1H), 6,80 (d, 1H), 3,90 (s, 3H).

Example 24

Intramuscular injection of 40 mg/ml

Injectable pharmaceutical preparation can be prepared by dissolving 40 g tetranitro apostoloi acid in water for injection (1000 ml) and subsequent sealing of the ampoule 1-10 ml

In order to determine the types of biological activity of the compounds below presents data for biological studies (table. 1) for the group are presented in the invention compounds in accordance with the method described in I. NatI. Cancer lnst.8i, 557 - 586 (1986).

The above results show that presents four compounds have antiviral activity and therefore are useful as antiviral agents, in particular anti-HIV agents.

Connection FCE 27968 is the first initial connection p. 4 claims, compound FCE 28176

the second connection of the same claim. Connection FCE 28832 can be found on page 48 rows 1-3, and the connection FCE 28856 - page 48 line 4-6 description of the application.

1. Ureidopropionic naphthaleneboronic acids of the formula I

< / BR>
where each of m and n that have the same values, is an integer from 1 to 4; each of p and q that have the same values, is an integer from 1 to 3, and each of the groups R, which have the same values, represents a free or esterified group, phosphonic acid, and their pharmaceutically acceptable salts.

2. -alkylbis ether.

3. The compound of formula I under item 1, where each of m and n is 2, each of p and q is the number 2 and each of the groups R, which are identical, is a free or C1-C6-alkyl - or phenyl-C1-C6-alkiltrimetilammony group, phosphonic acid, or their pharmaceutically acceptable salts.

4. Connection on p. 1, selected from the group consisting of carbonyl bis-3-({ 4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino] -1-methylpyrrole-2-carbonyl} amino)naphthalene-1,5-diphosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,7-diphosphonic acid;

carbonyl bis-3-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,6-diphosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,6-diphosphonic acid;

carbonyl bis-3-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5,7-diphosphonic acid;

carbonyl bis-2-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,5-diphosphonic acid;

carbonyl bis-1-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5,7-diphosphonic acid;

carbonyl bis-1-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5,6-diphosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5,6-diphosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-2,5-diphosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-6,7-diphosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-2,6-diphosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-2,7-diphosphonic acid;

carbonyl bis-1-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5-phosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-5-phosphonic acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-6-phosphonic acid;

carbonyl bis-1-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}am is-carbonyl}amino)naphthalene-2,5,6-triphosphonate acid;

carbonyl bis-4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,5,7-triphosphonate acid;

carbonyl bis-3-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl}amino)naphthalene-1,5,7-triphosphonate acid;

carbonyl bis-3-{/4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2-carbonyl} amino)naphthalene-1,5-diphosphonic acid;

carbonyl bis-4-{/4-/{(4-[4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2-carbonyl] amino} naphthalene-1,7-diphosphonic acid;

carbonyl bis-1-{ [4-/{(4-[4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl} amino)-1-methyl-2-carbonyl] amino}naphthalene-5,7-diphosphonic acid;

carbonyl bis-4-{ [4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2-carbonyl]amino}naphthalene-5,7-diphosphonic acid;

carbonyl bis-3-{ [4-({4-[(4-aminopyrrolo-1-methyl-2-carbonyl)amino]-1-methylpyrrole-2-carbonyl} amino)-1-methylpyrrole-2-carbonyl]amino}naphthalene-1,5,7-triphosphonate acids and their C1-C6-alilovic and phenyl-C1-C6-alilovic esters and pharmaceutically acceptable salts.

5. Pharmaceutical composition, oblad is the quality of the active component a compound of the formula I according to any one of paragraphs.1-4 or its pharmaceutically acceptable salt.

6. The compound of formula I according to any one of paragraphs.1-4 or its pharmaceutically acceptable salt for use as antiuniverse funds.

 

Same patents:

The invention relates to medicine, relates to the composition for parenteral administration and its preparation

The invention relates to new tizamidine pyridinylmethyl acids f-ly R2-Z-Q-(CR1R1)n-CH[P(O)(OH)2]2(I) where R1-H, -SH, -(CH2)mSH or-S-C(O)-R3, R3- C1-C8-alkyl, m = 1 - 6, n = 0 to 6, Q is a covalent bond or-NH-, Z - pyridinyl, R2- H, -SH, -(CH2)mSH, -(CH2)mS-C(O)R3or-NH-C(O)-R4-SH, where R3and m have the above meaning, R4- C1-C8-alkylen, or their pharmaceutically acceptable salts or esters

The invention relates to pharmaceutical industry and relates to a solid pharmaceutical composition risedronate for oral administration

The invention relates to medicine, in particular to rheumatology, and for the treatment of arthritis

The invention relates to a derivative of guanidine-1,1-bis phosphonic acid, method for their production and to their use

The invention relates to 2-sharonlee - 4,5,6,7 - tetrahydro-2-sharinaletisha-phosphonates and-Phosphinates, inhibiting enzymatic activity; to compositions containing these compounds, their use and the treatment of disruptive disorders, and to methods for their preparation
The invention relates to medicine and can be used to treat breast cancer stage III - IV

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, oncology, gynecology.

SUBSTANCE: method involves external irradiation and using chemopreparations combined with autoplasma. External irradiation in the dose 2 Gr is carried out from 1 to 4 day of treatment followed by intravenous administration of cisplatin on 5 day in the dose 10 mg with 250 ml of physiological solution. On the following day 10 ml of autoplasma incubated with 10 mg of cisplatin is administrated by paratumoral route by right and left of tumor into paravaginal cellular tissue and by intratumoral route into projection of cervical channel. Blood cellular elements are incubated with 600 mg of cyclophosphane and reinfused by intravenous drop route. Effects are repeated in indicated sequence once per a week, 4 times per treatment course. Method provides increasing percent of tumor regression due to the complex effect on tumor, enhancing the topical concentration of cytostatic drug and prolongation of its contact in malignant growth zone, and providing radiosensibilizing effect in diminishing the general toxic effect of therapy. Invention can be used in treatment of patients with topically disseminated forms of uterus cervix cancer at the stage T3NxM0.

EFFECT: improved and enhanced treatment method.

1 ex

FIELD: medicine.

SUBSTANCE: method involves incubating flasks containing 70-80 ml of blood and 40 ml of preservative agent for 20 min at 37°C together with chemotherapeutical preparations. Next to it, treatment with alternating magnetic field of 50 mTesla units intensity and frequency of 50 Hz is applied at continuous rotation about its axis at 20 rpm speed. 30 mg/m2 of Doxorubicin is added to the first flask contents. 500 mg/m2 of cyclophosphane are added to the second flask and 20 mg/m2 of methotrexate are added to the third flask. Incubation and treatment with alternating magnetic field is started with the first flask at the first and the eighth day. Total chemopreparations quantity is equal to 60-80 mg, cyclophosphan is applied in the amount of 1200-1600 mg, methotrexate - 40 mg.

EFFECT: enhanced effectiveness of treatment.

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating malignant tumors of mammary gland in case no tumor penetration into thoracic fasciae. The method suggested includes autohemochemotherapy. Moreover, on the 1st d of therapy it is necessary to sample 30 ml blood out of patient's peripheral vein into the 1st vial to combine its content with 500 mg 5-fluorouracil and 600 mg cyclophosphan; then one should sample 20 ml blood into the 2nd vial to combine its content with 40 mg doxorubicin; both vials should be incubated at 37-37.5 C for 20-30 min, afterwards its necessary to inject the mixtures out of both vials under the tumor and along its circumference. On the 8th d of therapy one should repeat impact procedures at the same dosages of anti-tumor preparations and at the same order. The innovation suggested enables to develop the largest concentration of anti-tumor preparations in lesion focus, divide into fragments, decrease tumor's size and its inflammatory component and border it against surrounding tissues for performing radical surgical treatment.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine.

SUBSTANCE: method involves introducing antitumor chemo preparations with blood components. To do it, 300 ml of patient autoblood is subjected to centrifuging during 20 min at 2200 rpm. The produced 150-200 ml of autoplasma and 100 ml of packed red blood cells are placed into separate reservoirs. Cys-platinum as single dose of 100 mg is incubated with the autoplasma and cyclophosphane as single dose of 1 g is incubated with the packed red blood cells. Single doxorubicin dose of 30-50 mg is concurrently introduced with one of the preparations. When combined with cis-platinum, doxorubicin is incubated with the packed red blood cells. When combined with cyclophosphane, doxorubicin is incubated with the autoplasma. Reinfusion is carried out to bring total dose of the preparations to 150 mg of doxorubicin, 3-5 g of cyclophosphane and 200 mg of cis-platinum. Pause between the procedures is 3-4 days long.

EFFECT: avoided risk of adverse side effects; increased preparation activity; accelerated treatment course.

FIELD: experimental medicine and oncology.

SUBSTANCE: claimed method includes intraperitoneum cyclophosphan administration in dose of 120 mg/kg and intravenous transplantation of fetal liver steam cells to experimental animal. Fetal liver steam cells are transplanted for 3 days before cyclophosphan administration in dose of 25x106 cells/kg of mass.

EFFECT: decreased tumor growth, reduced frequency and area of metastasis due to optimization of cyclophosphan and steam cells administration.

2 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of 1,3,2-oxazaphosphacycloalkane of the general formula (I):

wherein Y represents oxygen atom (O) or sulfur atom (S); n = 1, 2, 3 or 4; X represents hydroxamic acid or carboxylic acid; R2 represents hydrogen atom, (C1-C8)-alkyl, (C2-C6)-alkenyl or aryl-(C0-C6)-alkyl, and to their salts, hydrates or solvates. Proposed compounds are inhibitors of matrix metalloproteinases taking part in tissue degradation that suggests the possibility for their using in the human therapy and veterinary.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 tbl, 242 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating malignant tumors of different genesis. For this purpose one should intravenously inject electrolytic silver solution once or twice daily at the dosage of 0.05-0.1 mg/kg body weight against silver, the course being about 1-3 mo, or such injection of electrolytic silver solution should be altered every other day with cyclophosphan at accepted dosages. Application of electrolytic silver solution at present concentration provides pronounced decrease of tumor growth rate and enhanced apoptosis of tumor cells, moreover, higher efficiency of cyclophosphan without any manifestation of total toxic action.

EFFECT: higher efficiency of therapy.

3 tbl

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: after proving the pleural fluid sterility method involves its exfusion from pleural cavity and administration of antitumor chemopreparations. Firstly, 20 mg of bleomycetin is incubated with 20 ml of autopleural fluid, pleural fluid remained after exfusion is placed into packages "Gemakon" and centrifuged at 2000 rev/min for 60 min and liquid part is frozen. Pleural fluid is removed again as its accumulation and administration of incubated mixture of pleural fluid with bleomycetin is repeated also wherein the bleomycetin dose is increased up to 25 mg. In 2-3 days after removal of pleural liquid chemopreparations incubated with preliminary defrosted liquid part of pleural fluid are administrated each 5-7 days in the following sequence and doses: the first administration - 100 mg of cisplatin; the second administration - 100 mg of cisplatin; third, fourth and fifth administrations - 30 mg of doxorubicin and 1000 mg of cyclophosphan up to the total amount - cisplatin, 200 mg; doxorubicin, 90 mg, and cyclophosphan, 3000 mg. Method provides elimination of pleural fluid in full volume, to compensate loss of liquid, protein and trace elements, to reduce tumor size and to avoid toxic symptoms of chemotherapy. Invention can be used in the presence of exudative pleuritis in patients with lung cancer who can't to be subjected for operative and radiation treatment.

EFFECT: improved treatment method.

2 ex

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