Derivatives perosamine resides, and their pharmaceutically acceptable salts, method of production thereof and pharmaceutical composition having inhibitory angiogenesis activity

 

(57) Abstract:

Usage: in medicine as drugs with inhibitory angiogenesis activity. The inventive products derived perosamine resides formula I, where m and n are integers from 1 to 3, W is oxygen, B is a naphthalene or quinoline ring substituted by 1 to 3 sulfonic groups, or 2-deoxy-D-glucose-6-sulfate or 2-deoxy-D-glucose-6-phosphate and their pharmaceutically acceptable salts. Reagent 1 connection f-crystals 2, where n and B have the above values, the reagent 2 - compound of the formula X-C-/W/-X, where W is oxygen, X is halogen, imidazolidine, triazoline, n - nitrophenoxy or trichlorophenoxy. Reaction conditions: in a medium of an organic solvent in the presence of a base at a temperature from -10 to 50oC. 9 other 4 S. and 2 C.p. f-crystals, 1 PL.

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0

The invention relates to ureidopropionic substituted pyrrole to the method of production thereof and to pharmaceutical compositions containing these compounds. Paralowie compounds of the present invention may be considered as derivatives Distamycin A, which is a known compound of the formula:

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The specified Distamycin A described ("NATURE 203, 1064, 1964)s (I)

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where: m and n are the same and each is an integer from 1 to 3, W is oxygen or sulfur, group B are the same and each represents:

a) a saturated or unsaturated, carbocyclic or condensed carbocyclic core, substituted by one or more acid groups;

b) a saturated or unsaturated, heterophilically or heterobicyclic kernel containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and substituted one or more acid groups;

c) pyranyl or furnishing residue, substituted by one or more acid groups, or

d) -CH2(CHA)rCH2A-group, where A group may be the same or different and each represents an acid group, and r is an integer 0, 1 or 2, and their pharmaceutically acceptable salts.

If group B has two or more acidic groups defined above in (a), (b) and (c), they may be the same or different. In accordance with the definition of group B, the data in (a), (b), (c) and (d), the acid group can be selected from sulfonic acids, sulfuric acid, sulfamic acid, sulfinol KISH, SO3H2, SO2H, PO4H2, PO3H2, PO3NH3and CO2H.

Preferred groups B, in accordance with the definitions in (a), (b) and (c) are group substituted 1 to 3 mentioned acid groups.

If B is the kernel defined in (a), this kernel can be, for example phenyl or nafcillin. If B is the kernel defined in (b), it is the kernel, for example, it may be tetrahydropyranyl or tetrahydrofuranyl. If B is a sugar residue, defined in (c), this residue may, for example be from glucose or ribose.

If B is a group defined in (d), preferably, when r is 2.

As mentioned above, the scope of the present invention includes also pharmaceutically acceptable salts of compounds of formula (I).

Examples of pharmaceutically acceptable salts are either salts formed with inorganic bases such as sodium hydroxide, potassium, calcium and aluminum, or salts formed with organic bases such as lysine, arginine, N-methyl-glucamine, triethylamine, triethanolamine, dibenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N-ethylpiperidine, N,N-diamine organic amines.

Preferred compounds of the present invention are the compounds of formula (I), where: m and n are equal and each is equal to 2, W is oxygen, group B are the same and represent a') unsaturated carbocyclic or condensed carbocyclic nucleus, substituted 1-3 acid groups, b') tetrahydropyranyl or tetrahydrofuranyl core, substituted by 1-3 acid groups, or c') glucocerebrosidase residue, substituted 1-3 acid groups, as well as their pharmaceutically acceptable salts.

Specific examples of the preferred compounds of the present invention are the following compounds, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon (N-methyl-4,2-pyrrole)carbylamine))bis (1,3-naphthalenedisulfonic acid, 8,8'-(carbonyl-bisamino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine))bis(3,5 - naphthalenedisulfonic acid), 8,8'-(carbonyl-bisamino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,5 - naphthalenedisulfonic acid, 8,8'-carbonyl-bisamino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine))bis(2,4 - naphthalenedisulfonic acid), 8,8'-(carbonyl-bis-imino-N-methyl-4,2-terracarbon irratabile-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,6 - naphthalenedisulfonic acid), 8,8'-(carbonyl-bis-imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)-carbylamine))bis(3,6 - naphthalenedisulfonic acid, 8,8'-(carbonyl-bis-imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(1,5-naphthalenedisulfonic acid), 8,8'-(carbonyl-bis-imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(1-naphtalenesulfonic acid, 8,8'-(carbonyl-bis-imino-N-methyl-4,2-terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(3 - naphthalenesulfonate acid, 8,8'-(carbonyl-bis-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(5 - naphtalenesulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine))bis(1,3,5 - naphthalenesulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine))bis(1,4,6 - naphthalenesulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-4,2-pyrrole)carbylamine))bis(2,4,6 - naphthalenesulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine))bis(1,3,6- (naphthalenesulfonic acid), 8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine))bis(2,3,5-naftalis the 2-deoxy-D-glucose-6-sulfate), and 2,2'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine))bis-(2-deoxy-D-glucose-6-phosphate), and their farmatsevticheskii acceptable salt, especially the sodium and potassium salts.

Compounds of the present invention and their salts can be obtained in a way that is the fact that the compound of formula (II):

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where n and B are defined above, or its salt is subjected to reaction with the compound of the formula III:

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where W is defined above, and groups X may be the same or different, and each of them is a good leaving group, and optionally with subsequent transformation into a salt of the compounds of formula (I), and/or, if desired, followed by obtaining a free compound (I) from its salt.

Salts of compounds of formula (II) may be salts formed with inorganic bases, such as the above-mentioned pharmaceutically acceptable salts of the present invention, and preferred are salts of potassium and sodium.

In the definition of X, examples of good leaving groups are atoms halogen, in particular a chlorine atom, or other easily replaceable group such as imidazolyl, triazolyl, p-nitrophenoxy or trichlorophenoxy.

and processes and so this reaction can be carried out by known methods, for example in accordance with the terms described in the literature in organic chemistry for this type of reactions, i.e., for the synthesis of urea derivatives. Preferably, if the compound of formula (III), X is a halogen atom such as chlorine atom, and the reaction can be provided in a molar ratio of compound (II), or salts thereof, to the compound (III) comprising from about 1:1 to about 1:4. The reaction is preferably carried out in organic solvents, such as dimethylsufoxide, hexamethylphosphoramide, or their aqueous mixtures, or mixtures of water/dioxane or water/toluene and in the presence or organic bases such as triethylamine or diisopropylethylamine, or inorganic bases, such as sodium bicarbonate or sodium acetate. The reaction temperature can vary from about -10oC to About 50oC, and the reaction time is from about 1 to about 12 o'clock

The compounds of formula (I) obtained in accordance with the above procedures can be purified by standard methods such as column chromatography on silica gel or aluminum oxide, and/or recrystallization from organic solvents, I of formula (I) can be carried out by standard methods.

The compounds of formula (II) can be obtained by standard methods. For example, the compound of formula (II) can be obtained by recovering the compounds of formula (IV):

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where n and B are defined above, in accordance with standard procedures, well known to specialists. The compound of formula (IV) can be obtained by the reaction formula (B-NH2where B is defined above, with a compound of formula (V):

< / BR>
where n and X are defined above.

The reaction of the amine of formula B-NH2with the compound of the formula V is also a well-known process.

Alternatively, the compound of formula (IV), where n is 2 or 3, can be obtained by using multi-stage process involving the reaction of the compound of formula (VI):

t

where X is defined above, with an amine of formula B - NH2where B is defined above. As a result of the reaction which can be carried out by standard methods, obtain the compounds of formula (VII):

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where B is defined above.

The compound of formula (VII) restore standard methods, resulting in the receive connection of the formula (VIII):

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where B is defined above, which, in turn, is subjected to reaction with the compound of the formula (Timo to obtain the compound of formula (IV), where n is 3, then this requires subsequent recovery phase acylation.

The compounds of formula (V) is known compounds and can be obtained, for example by the method described in Heterocycles", T. 27, N 8, 1988, S. 1945 52).

The compounds of formula (VI) and the amine of formula B-NH2are known products and can be taken off the shelf, or they can be obtained by standard methods.

Pharmacology.

It was found that the compounds of the present invention are active inhibitors of angiogenesis.

The inhibitor of angiogenesis is a substance having the ability to suppress the growth of new blood vessels. Therefore, compounds of the present invention can be used for the treatment of certain pathological conditions in mammals, including humans, in which the growth of new blood vessels has a detrimental impact on the condition of the body, and, specifically, for the treatment of chronic inflammatory diseases, diabetic retinopathy, psoriasis, rheumatoid arthritis, and tumor growth. In particular, for anti-cancer therapy, the compounds of the present invention can be introduced separately or in acetamid, bleomycin, vinblastine or mitomycin. Inhibitory activity against angiogenesis compounds of the present invention was protomodular the fact that these compounds found activity in the test for chorioallantoic membrane (SAM analysis) conducted in accordance with the method of Volkmann [Nature 297, 307 (1982)]

Test chloromelanite membrane (CAM assay).

Chicken embryos were separated from the shell on day 3 of development, placed in plastic Petri dishes and maintained at 37oC, 3% CO2. On day 5 embryos were treated with saline or subjects molecules introduced into the pill in 5% methylcellulose was placed on top of the growing CAM. The group of nine eggs were used for each dose.

After 48 h, the embryos were examined using a stereomicroscope at a hundred-fold increase in the presence or absence of capillaries around the membrane. Were considered positive embryos, representing the vascular zone with a diameter of at least 4 mm

The results are shown in the table in the form of positive CAM at the tested concentration.

The table shows that the group of compounds of the invention are capable ingibiruyutheyj conditions. Tested compounds in the table identified as "FCE", as used in the examples.

In addition, it was found that the compounds of the present compounds has TNFneutralizing activity, and therefore they can be used in the prophylaxis and/or treatment for any medical conditions of the person in which TNFas it is known, plays an unfavorable role. Generally, such conditions are cachexia, septic shock, graft versus host disease, AIDS, cerebral malaria, revmatoidnyi arthritis. TNFinhibiting activity of the compounds of the present invention may be illustrated, for example, the fact that they are active in the inhibition of the cytotoxic action of TNFman on raw mouse LM cells.

Compounds of the present invention can be introduced in the usual ways, for example parenterally, i.e., by intravenous infusion or injection, intramuscular injection, subcutaneous injection, by topical application or oral. The dose varies depending on age, weight and condition of the patient, as well as a way of introduction.

For example, a suitable single dose for an adult man to be placed may include from 5 to 80 wt. the compounds of formula (I) as an active ingredient in combination with one or more pharmaceutically acceptable excipients and/or carrier in the amount of 20 to 95 wt.

The pharmaceutical compositions of the present invention can be obtained by standard methods and introduced in the form of pharmaceutically acceptable dosage forms.

For example, solutions for intravenous injection or infusion can include sterile water or preferably they can be made 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 corresponding number of hydrochloride lidocaine.

Medicines for external use can be made in the form of creams, lotions or pastes for skin treatment, for example by mixing the active ingredient with standard oil or emulsifying fillers.

Medicines for oral administration can be izgotovleniju, saccharose, cellulose, corn and potato starch, sizing, for example silica, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols, binding agents, e.g. starches, Arabic gums, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, desagregirutee agents, for example starch, alginic acid, algina, gluconat sodium, starch, gasiouse mixture, colorants, sweetening agents, wetting agents, for example lecithin, Polysorbate, laurylsulphate, and, mostly, non-toxic and pharmacologically inert substance, commonly used in pharmaceutical compositions. These pharmaceutical preparations may be manufactured in a standard way, for example by mixing, granulating, tabletting or sugar coating or film coating.

In addition, the present invention relates to a method of treatment of pathological conditions in which the growth of new blood vessels is an unfavorable factor, such as chronic inflammatory diseases, diabetic retinopathy, psoriasis, rheumatoid arthritis and tumors, and the specified method is that the milk is altoadige of the invention are also products containing the compound of formula (I) or its pharmaceutically acceptable salt, and a biologically effective amount of another active substance is manufactured in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of diseases in which TNFhas an adverse effect.

The term "combined" treatment means as a separate and, mainly, the simultaneous introduction of a composition containing a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, and a pharmaceutical composition comprising a therapeutically effective amount of another active pharmaceutical substances.

The type of active substance, which can enter the pharmaceutical composition with a compound of the present invention, or alternatively, which may be introduced combined method of treatment depends on the extent of disease, such substance may be gamma globulin, immunoglobulin and monoclonal antibody, antibiotics and antimicrobial agents. Typically, the antimicrobial agents are a penicillin, in combination with an aminoglycoside, for ephalosporins.

The following examples illustrate the present invention but do not restrict it.

Example 1. 8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis (1,5 - naphthalenesulfonate acid), Terentieva salt (FCE-26492).

To a solution of centripetality 8-(amino-N-methyl-4,2-terracarbon-imino(N-methyl-4,2-pyrrole)carbylamine) (1,5 - naphthalenesulfonate acid) (0.6 g 1,0210-3M) in water (20 ml) was added, while stirring, sodium acetate (0,328 g, 4 mm). The mixture was cooled to 0oC in an ice salt bath, and then one drop of solution was added pashennaya (1,4 ml, 4 EQ.). The resulting mixture was stirred at 0oC for 1 h, the Solvents evaporated in vacuo, and the residue was dissolved in methanol and filtered. The filtrate is evaporated, and the residue was subjected to column chromatography on silica gel, elwira mixture of methylene chloride and methanol (60:40), which was obtained 0.16 g of the target compound.

IR (KBR) cm-1: 3440 Shir. 1660, 1640, 1585, 1180, 1030,

NMR (DMSO d6): d of 3.84 (3H, s), 3,85 (3H, s), to 6.80 (1H, d), 7,07 (2H, m), 7,41 (2H, m), 7,92 (2H, DD), to 8.12 (1H, s), of 8.27 (1H, DD), 9,07 (1H, DD), for 9.90 (1H, Shir.C), 12,27 (1H, Shir.C), F. A. B. M. S: M/Z: 1209, M++ 1, 1231, M++ 23, 1128, M-80, U. F. (H2O) N. M. lmax(E1%l-bis(imino-N-methyl-4,2-pyrrole-carbylamine (N-methyl-4,2-pyrrole)carbylamine)) bis(3-naphtalenesulfonic acid), disodium salt,

IR(KBR) cm-1: 3430 Shir. 1460, 1585, 1200, 1030,

NMR (DMSO-d6): 3,84 (6N, C) 6,86 (1H, d), 7,05 (1H, d), from 7.24 (1H, d), 7,35 (1H, d), 7,54 (2H, m) of 7.70 (1H, DD), 8,15 (1H, d), of 8.95 (1H, Shir. C.), 9,94 (10H, Shir. C) there is a 10.03 (1H, Shir.S.),

F. A. B. M. S: M/Z: 1005, M+, +H, 1027, M++Na,

U. F. (H2O) N. M. lmax(E1%1 cm): 304 (366), 226 (1002).

8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrroloquinoline (N-methyl-4,2-pyrrole)carbylamine)) bis(1-naphtalenesulfonic acid), disodium salt (FCE 27235),

NMR (DMSO-d6): of 3.84 (3H, s), 3,85 (3H, s), PC 6.82 (1H, d, J 1,8), 7,06 (1H, d, J 1,8), TO 7.09 (1H, d, J 1,8), 7,39 rate of 7.54 (3H, m), 7,74(1H, DD, J 1,3, J 8,2) 7,93-8,02 (2H, m), 8,13 (1H, sh.C), compared to 8.26 (1H, DD, J 1.5 AND J 7,3), TO 9.93 (1H, CL), 12,20 (1H, CL),

F. A. B. M. S: M/Z: 1005, M++H, 1027, M++Ne,

U. F. (H2O) p. M. lmax(E1%1 cm): 312 (490), 224 (831).

8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(5-naphthalenesulfonic acid), disodium salt (FCE-27245),

NMR (DMSO-d6): 3,85 (6N, (C), at 6.84 (1H, d, J 1,8), 7,05 (1H, d, J 1,8), 7,25 (1H, d J 1,8), 7,35 (1H, d J 1,8), 7,46 7,56 (3H, m), 7,92 -8,00 (2H, m), 8,15 (N, CL), 8,87 (1H, m), of 9.89 (1H, CL), there is a 10.03 (1H, CL),

F. A. B. M. S: M/Z: 1005, M++H, 1027, M++ Ne, 538, 512,

U. F. (H2O) p. M. lmax(E1%1 cm): 310 (531), 227 (1043).

8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-(N-methyl-4,2-the 84 (3H, C), 3,86 (3H, s), for 6.81 (1H, d, J 1,8), WAS 7.08 (2H, CL), 7,41 (1H, d, J 1,8), TO 7.50 (1H, t, J 7,0), 7,78 (1H, d, J 7,0), 8,02 (1H, d, J 7,0), 8,11 (2H, m), 8,53 (1H, d, J 2,0), TO 9.93 (1H, CL), 12,21 (1H, CL),< / BR>
F. A. B. M. S: M/Z: 1209, M++ H, 1231, M++ Ne, 1187, M+Ne + H, 1129, 640, 618, 614, 592,

U. F. (H2O) p. M. lmax(E1%1 cm): 309,05 (403), 229,65 (735).

8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrocarbonate-(N-methyl-4,2-pyrrole)carbanilide)) bis(3,5 - naphthalenedisulfonic acid), Terentieva salt (FCE-27234),

NMR (DMSO-d6): 3,85 (6N, (C), 6,83 (1H, d, J 1,8), 7,06 (1H, d, J 1,8) 7,26 (1H, d, J 1,8), 7,38 (1H, d, J 1,8), TO 7.50 (1H, d, J 7,8), 7,72 (1H, D. d, J 8,9), 7,98 (1H, d, J 7,8), TO 8.25 (1H, CL), 9,19 (1H, d, J 1,7), to 9.91 (1H, c), there is a 10.03 (1H, c),

F. A. B. M. S: M/Z: 1209, M++ H, 640, 618, 614, 592,

U. F. (H2O) p. M. lmax(E1%cm): 310 (431), 231 (1027).

8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,5 - naphtalenesulfonic acid), TETRANITRATE salt,

8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-methyl-(4,2-pyrrole)carbylamine)) bis(2,4 - naphthalenedisulfonic acid), Terentieva salt,

NMR (DMSO-d6): 3,85 (6N, (C), for 6.81 (1H, d, J 1.7 Hz), 7,06 (1H, d, J 1 + H), 7,25 (1H, d, J 1.7 Hz), 7,34 (1H,d, J 1.7 Hz), 7,4-7,6 (2H, m), 8,14 (1H, CL), of 8.25 (2H, s), 8,73 (1H, DD, J 1,3 H2J of 8.3 Hz), 9,92(1H, CL), 10,07 (1H SHS),

F. A. B. M. S: M/Z: 1209 (M++1), 1231 (M++ Ne), 1-methyl-4,2-terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine))bis(1,6-naphthalenedisulfonic acid), Terentieva salt,

8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,2 - naphthalenedisulfonic acid), Terentieva salt,

8,8'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(3,6 - naphthalenedisulfonic acid), Terentieva salt.

Example 2. 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(1,3,5 - naphthalenesulfonic acid), hexanetriol salt (FCE-26605).

To a solution of hydrochloride of 8-(amino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine))(1,3,5 - naphthalenesulfonic acid trinational salt) (2,19 g, 3M) in water (60 ml) and dioxane (15 ml) was added, hanging, sodium acetate (0,984 g, 12 mm). The mixture was cooled to 8oC ice bath, and then drop by drop in the course of 1 h was added a 20% solution of phosgene in toluene (3 ml, approximately 6 mm), diluted with 9 ml of dioxane. The resulting mixture was stirred at the 8oC for 2 h, the Solvents evaporated in vacuo, and the residue was dissolved in methanol.

After filtration of the salts, the filtrate evaporated and the residue was chromatographically on a column of silica gel, elwira mixture of methylene chloride, methanol and the 1030

NMR (DMSO-d6) of 3.80 (3H, s) a 3.83 (3H,s) to 6.80 (1H,d), 7,06(2H,m), 7,40 (1H,d) 7,88 (1H,d)8, to 7.99 (1H, d), 8,02 (1H, Shir.(C) to 8.57 (1H,d), was 9.33 (1H,d) to 9.91 (1H, Shir.C) 12,29 (1H, Shir.C).

FAB-MS M/Z 1411, m-H, 1389, M-- Na

UV (N2O) nm lmax(E1%1 cm) 311 (266) 233(551).

The same method can be obtained the following compounds:

8,8'-(carbonyl-bis)imino-N-methyl-4,2-errorcorrecting(N-methyl-4,2-perrl)carbylamine)) bis(1,4,6 - naphthalenesulfonic acid), hexanetriol salt,

8,8'-(carbonyl-bis(imino-N-methyl-4,2 - pyrocarbonic-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,4,6 - naphthalenesulfonic acid), hexanetriol salt,

8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(1,3,6 - naphthalenesulfonic acid), hexanetriol salt (FCE-26752),

NMR (DMSO-d6): 3,84 (3H, c), 3,88 (3H,c), is 6.61 (1H, d, J=1,8), 7,07 (1H,d, J=1,8), 7,11 (1H, d, J=1,8), 7,42 (1H, d, J=1,8), 7,87 (1H, d, J=1,9), of 8.06 (1H, d, J= 1,9), to 8.12 (1H, CL), with 8.33 (1H, d, J=1,9), 8,54 (1H, d, J= 1,9), to 9.93 (1H, CL), 12,19 (1H, CL),

U. F. (H2O) p. M. lmax(E1%1 cm):309(314), 235 (793).

8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,3,5-naphthalenesulfonic acid), hexanetriol salt,

7,7'-(carbonyl-bis(imino-N-methyl-4,2 - pyrrole) - Rev.,15 (DD, J=1.9 Hz, 2H), 7,87 (m, 2H), 8,00 (d, J=1.7 Hz, 1H), 8,17 (s, 1H), they were 8.22 (d, J=1.7 Hz, 1H), of 8.90 (s, 1H), 10,08 (C. 1H).

7,7'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon) (N-methyl-4,2-terracarbon(N-methyl-4,2 - pyrrole)carbylamine)) bis-(1,3-naphthalenedisulfonic acid), tetraclita salt,

'H-NMR(200 MHz, DMSO):d 3,84, 3,86, 3,88 (three, N), to 6.80 (d, J=1.7 Hz, 1H), 7,05 (m, 2H),7,20 (d, J=1.6 Hz, 1H), 2,75 (d, J=1.6 Hz, 1H), 7,34 (d, J= 1.6 Hz, 1H), 7,87 (m, 2H), 7,80 (d, J=1.7 Hz, 1H), is 8.16 (s, 1H), 8,21 (d, J=1.7 Hz, 1H), of 8.95 (s, 1H), 9,85, 9,99, 10,23 (three s, 3H).

Example 3. 8-(amino-N-methyl-4,2-terracarbon-imino(N-methyl-4,2-pyrrole, carbylamine))(1H, 3,5-naphthalenesulfonic acid trinacria salt, hydrochloride,

8-(nitro-N-methyl-4,2-terracarbon-imino(N-methyl-4,2-pyrrole)carbylamine)) (1,3,5-naphthalenesulfonic acid chinatravel salt) (2.17 g=3 mm) was dissolved in a mixture of water (120 ml) and 1 n HCl (3 ml) and subjected to reaction recovery in the presence of Pd-catalyst (10% on charcoal, 900 mg) at a pressure of H250 psi (345 kPa) for 3 h

The catalyst was filtered and the remaining solution was concentrated in vacuum to dryness, which was obtained 2.1 g of the target compound.

IR(KBR) cm-1:3440 Shir. 1640, 1520, 1190, 1030,

NMR (DMSO-d6): d of 3.85 (3H,s), 3,90 (3H,s), and 7.1 (3H,m), and 7.4 (1H,d), 7,95 (2H, m), at 8.60 (1H,decarbonylation)) (1,3,5-naphthalenesulfonic acid trinacria salt). To a solution of hydrochloride of 8-(amino-(N-methyl-4,2 - pirrolilborana)(1,3,5-naphthalenesulfonic acid trinational salt))(1,824 g, 3 mm) in water (45 ml) and 1 n NaOH (1 ml) stirring, was added sodium acetate (0, 492 g 6 mm). The solution was cooled in an ice bath at 5oC, after which it drop by drop in the course of 1 h was added (4-nitro-N-methyl-2-pyrrole)carbonylchloride (0,567 g 3 mm) in dioxane (30 ml). The mixture is stirred for 1 h at 5oC, acidified to pH 4 with I n HCl and evaporated in vacuum to dryness. The residue was treated with ethyl acetate (300 ml), stirred for 1 h and filtered, resulting in a received target connection 2,1,

IR (KBr)cm-1:3440 Shir. 1650, 1520, 1305, 1195, 1030

NMR (DMSO-d6, 80 MHz) d:the 3.89 (3H,s) to 3.99 (3H,s) to 7.18 (1H, d) 7,46 (1H, d) of 7.70 (1H,d), 8,02 (2H,m) to 8.2 (1H,d), 8,63 (1H,d), 9,41 (1H,d), 10,45 (1H, Shir.C) 12,42 (1H, Shir. C).

Example 5. 8-(amino-(N-methyl-4,2-pyrrole)carbylamine)(1,3,5 naphthalenesulfonic acid trinacria salt), hydrochloride.

A solution of 8-(nitro-(N-methyl-4,2 pyrrole) carbylamine) (1,3,5-naphthalenesulfonic acid trinational salt)(1,803 g=3 mm) in water (120 ml) and 1 n HCl (3 ml) was restored in the presence of catalyst (10% Pd on charcoal, 800 g) under hydrogen pressure of 50 psi (345 kPa)for 4 h

Katal is avago connection.

IR (KBR) cm-1: 3440 Shir. 1640, 1520, 1190, 1030,

NMR (DMSO-d6): d of 3.9 (3H, s), 7,11 (1H, d), 7,29 (1H, d), of 8.04 (2H, m), and 8.6 (1H, d), 9,88 (1H, d), 10,04 (3H, Shir. C), KZT 12.39 (1H, Shir.C).

Example 6. 8-nitro-(N-methyl-4,2-pyrrole)carbylamine) (1,3,5-naphthalene-trisulfonic acid trinacria salt).

To a solution of trinational salt of 8-amino-1,3,5-naphtalenesulfonic acid (1,347 g 3 mm) in water (45 ml), stirring, was added sodium acetate (0,492 g 6 mm). The solution was cooled in an ice bath at 5oC, then for 1 h at the drop of solution was added (4-nitro-N-methyl-2 - pyrrole)carbonylchloride (0,943 g 5 mm) in dioxane (45 ml).

The mixture is stirred at 5oC for 3 h, acidified to pH 4 with 1N HCl and evaporated in vacuum to dryness. The residue was treated with ethyl acetate (300 ml), stirring for 1 h and filtered, resulting in a received 1.7 g of the target compound.

IR (KBR) cm-1: 3440 Shir. 1650, 1530, 1305, 1200, 1030,

NMR (DMSO-d6): d of 3.96 (3H, s), to 7.84 (1H, d), of 8.06 (2H, m), 8,15 (1H, d), 8,63 (1H, d), and 9.4 (1H, d), 12,55 (1H, Shir.C).

Example 7. 7,7'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon)-imino(N-methyl-4,2-pyrrole)carbylamine) bis(1,3 - naphtalenesulfonic acid), Terentieva salt (FCE-26644).

To a solution of the hydrochloride of 7-(amino-N-methyl-4,2-Pyrrhus) in water (15 ml) and dioxane (10 ml), stirring was added potassium acetate (50 mg, 0.51 mm). Then at room temperature for half an hour one drop was added a 20% solution of phosgene in toluene (0.5 ml, approximately 1 mm), diluted with dioxane 2 ml of the resulting mixture was stirred at room temperature for 1 h, the Solvents evaporated in vacuo, the residue was chromatographically on a column of silica gel, elwira mixture of methylene chloride, methanol and water (40 40 6), which received 90 mg of the target compound.

IR (KBR) cm-1: 3450 Shir. 1650, 1580, 1530, 1190, 1030

NMR (DMSO-d6): d of 3.84 (3H, s), a 3.87 (3H, s), to 6.80 (1H, d), 7,05 (1H, d), 7,18 (1H, d), 7,33 (1H, d), 7,86 (2H, m), of 8.00 (1H, d), 8,16 (1H, Shir.C), 8,21 (1H, d), of 8.95 (1H, Shir.C) 9,86 (1H, Shir.C) of 10.21 (1H, Shir.C).

UV (H2O) nm lmax(E1%1cm): 316,8 (371), 248,95 (444)

Fab-MS: M/Z:1273(M++H), 1311 (M++K).

Similarly can be obtained the following compounds 7,7'-(carbonyl-bis-imino-N-methyl-4,2-terracarbon(-N-methyl-4,2-pyrrole)carbylamine))bis(1-naphthalene-sulfonic acid), disodium salt,

7,7'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon(N-methyl-4,2-pyrrole)carbylamine)) bis(2 - naphthalenesulfonate acid), disodium salt,

7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole-carbanionic-bis(imino-N-methyl-4,2 - pyrocarbonic-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(4-naphthalenesulfonate acid), disodium salt,

7,7'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,3 - naphthalenedisulfonic acid), Terentieva salt,

7,7'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,4-naphthalene-disulfonate acid), Terentieva salt (FCE-27302),

NMR (DMSO-d6): of 3.85 (3H, s) to 3.89 (3H, s), for 6.81 (1H, d, J 1.7) AND 7,06 (1H, d, J 1,7), 7,22 (1H, d, J 1,7), 7,33 (1H, d, J 1,7), 7,38 (1H, DD, J 2,0, J 9,5), 7,92 (1H, CL), 8,10 (1H, d, J 1.7) AND TO 8.20 (1H, CL), 8,32 (1H, d, J 2,0), 8,69 (1H, d, J 9,4), 9,88 (1H, CL), 10,08 (1H, CL).

7,7'-(carbonyl-bis)(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(1,5 - naphthalenedisulfonic acid), Terentieva salt,

7,7'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,5-naphthalenedisulfonic acid), Terentieva salt,

7,7'-(carbonyl-bis(imino-N-methyl-4,2 - terracarbon-imino-(N-methyl-4,2-pyrrole)carbylamine)) bis(3,5 - naphthalenedisulfonic acid), Terentieva salt (FCE-27481),

NMR (DMSO-d6): d of 3.85 (3H, s), 3,90 (3H, s), for 6.81 (1H, d, J 1,8), OF 6.90 (1H, d, J 1,8), 7,12 (1H, d, J 1,8), 7,32 (1H, d, J 1,8), OF 7.70 (1H, DD, J 1.6, THE J 5,6), 7,80 (1H, d, J 8,6), 8,11 (1H, d, J 1,6), 8,15 (1H, CL), 8,58 (1H, d, J 1.7) AND 8,78 (1H, d, J 1.7) AND OF 10.05 (1H, CL), 10,94 (1H, CL),

F. A. B. M. S: M/Z 1209, M
7,7'-carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine) bis(2,6 - naphthalenedisulfonic acid), Terentieva salt,

7,7'-carbonyl-bis(imino-N-methyl-4,2 - terracarbon-(N-methyl-4,2-pyrrole)-carbylamine) bis(3,6-naphthalenedisulfonic acid), Terentieva salt (FCE-26939),

NMR (DMSO-d6): 3,85(3H, c), 393 (3H, c) for 6.81 (1H, d, J 1,8), 6,91 (1H, d, J 1,8), was 7.08 (1H, d, J 1,8), 7,51 (1H, d, J= 1,8), to 7.68 (1H, DD, J 1.6, The J 8,6), 7,78 (1H, d, J 8,6), of 8.04 (1H, c) to 8.12 (1H, CL), 8,23 (1H, s) 8,89 (1H, s), 10,02 (1H, CL), 10,98 (1H, CL),

F. A. B. M. S: M/Z: 1209,M++ H, 1187, M+-Na+H,

The UV. (H2O), p. M. lmax(E1%1 cm): 323,4 (540), 227,7 (732).

7,7'-carbonyl-bis(imino-N-methyl-4,2 - pyrrolinone-imino-(N-methyl-4,2-pyrrole)carbylamine)bis(1,3,5 - naphthalenedisulfonic acid), hexanetriol salt (FCE-27164),

NMR (DMSO-d6): of 3.85 (3H, s) to 3.89 (3H, s), is 6.78 (1H, d, J 1,8), was 7.08 (1H, d, J 1,8), 7,22 (1H, d, J 1,8), 7,35 (1H, d, J 1,8), to 8.25 (1H, d, J= 1,9), 8,30 (1H, CL), at 8.36 (1H, CL), of 9.00 (1H, CL), 9,07 (1H, d, J=1,6), 9,82 (1H, CL), and 10.20 (1H, CL),

U. F. (H2O) p. M. lmax(E1%1 cm): 320 (374), 254 (444).

7,7'-carbonyl-bis(imino-N-methyl-4,2 - terracarbon-(N-meteo-4,2-pyrrole)carbylamine)) bis(1,4,6 - naphthalenesulfonic acid), hexanetriol salt,

7,7'-carbonyl-bis(imino-N-methyl-4,2 - terracarbon the 7,7'-carbonyl-bis(imino-N-methyl-4,2 - terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(1,3,6 - naphthalenesulfonic acid), hexanetriol salt,

7,7'-carbonyl-bis(imino-N-methyl-4,2 - terracarbon(N-methyl-4,2-pyrrole)carbylamine)) bis(2,4,6 - naphthalenesulfonic acid), hexanetriol salt,

7,7'-carbonyl-bis(imino-N-methyl-4,2 - terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(2,3,5 - naphthalenesulfonic acid), hexanetriol salt,

2,2'-carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(2-deoxy-D-glucose-6 - sulfate);disodium salt,

2,6'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(2-deoxy-D-glucose-6-phosphate):disodium salt,

5,5'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N - methyl-4,2-pyrrole)carbylamine)) bis(8-hyalinella acid), disodium salt,

5,5'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(6-hyalinella acid), disodium salt,

8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole)carbylamine)) bis(5,7-hinolincarbonova acid), Terentieva salt,

5,5'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon - N-methyl-4,2-pyrrole)carbylamine)) bis(6,8-hinolincarbonova acid), Terentieva Sol is C(1,3,5 - naphthalenesulfonic acid).

The solution hexanetriol salt 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon(N-methyl-4,2 - pyrrole)carbylamine)) bis(1,3,5-naphthalenesulfonic acid) (400 mg) in water (10 ml) was chromatographically on column Amberlite IR-12OH (20 ml), elwira water. The solution is evaporated to dryness in a vacuum and was obtained 0.3 g of the target compound.

Example 9. Intramuscular injection of 40 mg/ml

Pharmaceutical preparation for injection can be made by dissolving 40 g hexanetriol salt 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole-carbylamine(N-methyl-4,2-pyrrole)carbylamine)) bis(1,3,5-naphthalenesulfonic acid in water for injection (1000 ml), after which the ampoule (1-10 ml) was tightly sealed.

1. Derivatives perosamine resides the General formula I

< / BR>
where m and n are the same, each an integer from 1 to 3;

W is oxygen;

In-groups are the same, each of them naphthalene or quinoline ring substituted by 1 to 3 sulfonic groups, or 2-deoxy-D-glucose-6-sulfate, or 2-deoxy-D-glucose-6-phosphate,

and their pharmaceutically acceptable salts.

2. Connection on p. 1 of the formula I, characterized in that in them m and n are equal and each is equal to 2, In-groups are the same, each and the ptx2">

3. Connection on p. 1, selected from the group consisting of the following compounds: 8,8'-(carbonyl-bis(N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(1,3-naphthalenedisulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole (carbylamine))bis(3,5-naphtalenesulfonic acid), 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2 - pyrrole)carbylamine))bis(2,5-naphthalenedisulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon(N-methyl-4,2-pyrrole) carbylamine))bis(2,4-naphthalenedisulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon(N-methyl-4,2-pyrrole) carbylamine))bis(1,6-naphthalenedisulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-imino-(N-methyl-4,2-pyrrole) carbylamine))bis(2,6-naphthalenedisulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine)bis(3,6-naphthalenedisulfonic acid), 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(1,5-naphthalenedisulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(1-naphtalenesulfonic acid), 8,8 the acid), 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(5-naphtalenesulfonic acid, 8,8'-carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(1,3,5-naphthalenesulfonic acid), 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(1,4,6-naphthalenesulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine)bis(2,4,6-naphthalenesulfonic acid), 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(1,3,6-naphthalenesulfonic acid, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon(N-methyl-4,2-pyrrole) carbylamine))bis(2,3,5-naphthalenesulfonic acid), 2,2'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(2-deoxy-D-glucose-6-sulfate), 2,2'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon-(N-methyl-4,2-pyrrole) carbylamine))bis(2-deoxy-D-glucose-6-phosphate), 7,7'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon(N-methyl-4,2-pyrrole) carbylamine))bis(1,3-naphthalenedisulfonic acid, 7,7'-(carbonyl-bis(imino-N-methyl-4,2-terracarbon)bis(1,3 - naphthalenedisulfonate), 7.7 imino)) bis (1,3-naphthalenedisulfonate), and their pharmaceutically acceptable salts.

4. Pharmaceutically acceptable salt of the compound according to any one of paragraphs. 1 3, which is a sodium or potassium salt.

5. The method of obtaining the compounds of formula I or its pharmaceutically acceptable salts, as claimed in PP. 1 4 claims, characterized in that the compound of formula II

< / BR>
where n and In are the specified values,

or its salt is subjected to the reaction of interaction with the compound of the formula III

< / BR>
where W is the specified value;

groups X are identical or different, each is a halogen atom or imidazolidine, triazoline, p-nitrophenoxy or trichlorophenoxypropionic,

and the resulting compound of formula I is optionally converted into its salt and/or optionally receive a free compound of formula I from its salts.

6. Pharmaceutical composition having inhibitory angiogenesis activity, containing the active ingredient and a pharmaceutically acceptable carrier and/or diluent, wherein the active ingredient it contains an effective amount of the compounds of formula I or its pharmaceutically acceptable salt according to PP. 1 4.

 

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The inventive compound is a derivative of the heterocyclic system thiazolo/5,4-in/indole type a:

< / BR>
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FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

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

3 cl, 5 dwg

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