Treasasturgis anionic compounds and pharmaceutical composition based on them

 

(57) Abstract:

Describes the new treasasturgis anionic compounds of General formula (I), where a represents a radical selected from the group comprising a, b, C, d; C' is selected from the SO3H or COOH;' is selected from NR1or, where R1selected from H or (C1-C6) alkyl straight or branched chain; X is selected from CL or radical F, where U' is selected from the group comprising-SO2- or-CO-, -NHC(O) or-NHC(S)-; W is selected from the radicals (i) or (ii) where Y represents -(CH2)n; n = 0-6; m = 0-2; Z is selected from H, CH2HE, COOH or CONR2R2where R2in each case independently selected from H or (C1-C6)alkyl, or pharmaceutically acceptable salt or ester. Compounds suitable for the treatment of viral infections, particularly infections caused by respiratory syncytial virus. Also described pharmaceutical composition based on them. 2 C. and 40 C.p. f-crystals, 4 PL.

The present invention relates to a new anionic compounds containing a triazine ring, which are used in the treatment of viral infections, particularly infections caused by respiratory syncytial virus human (RSWC). The present invention also Rel is the CTL of the INVENTION

Respiratory syncytial virus human (RSWC) was for the first time in 1956, is widely distributed around the world. It is an important cause of diseases of the upper and lower respiratory tract, causing disease in infants and young children, resulting in approximately 100,000 hospitalizations and 5,000 deaths in the United States annually (Chanock, R. M., Kim, H. K., Brandt, C. D. and Parrott, R. H. 1982. Respiratory syncytial virus, pp. 471-489, in Viral Infections of Humans, Second Edition, A. S. Evans, editor (Plenum Press, NY). Glezen, W. P., Taber, L. H., Frank, A. L. and Kasel, J. A. , 1986. Risk of primary infection and reinfection with respiratory syncytial virus. Am. J. Dis. Chil. 140; 543-546. MacDonald, N. E., Hall, C. B. , Suffin, S. C., Alexson, C., Harris, P. J., and Manning, J. A. 1982. Respiratory syncytial virus infection in infants with congenital heart disease. New England Journal of medicine 307; 397-400.

About 30% of hospitalized young children with acute respiratory illness have an infection due to respiratory syncytial virus human. In older children and in adults the disease is less severe. RSWC, apparently, is one of the main reasons (along with the flu) morbidity and mortality in the elderly (Fleming, D. M., and Cross, K. W. , 1993. Respiratory syncytial virus or influenza? Lancet 342; 1507-1510).

Infections caused by respiratory syncytial virus, can relate to all segments sulking clinically as bronchitis, inflammation of the bronchioles, pneumonia, lobar pneumonia or viral infection. In older children and in adults, the virus is usually limited replication in the upper respiratory tract. Babies can get sick in a more acute form, when the virus spreads to the lungs. Lung disease can be chronic.

Primary infection with respiratory syncytial virus occurs in early life, usually before the age of 4 years. Among children, the disease caused by this virus tends to occur at least once per year in the form of a rather distinct bouts lasting several months. Epidemics are sharply limited in time, usually within 3 to 5 months. Studies in families, children, students of Junior classes often bring the virus home, infecting younger family members more seriously than the rest of the family. Clinical consequences of infection are more severe when the first contact and become softer in older individuals who are immunologically protected.

The effects of respiratory syncytial virus can manifest itself in the form invisible from infection to severe pneumonia and soulsista cases occurs after one to three weeks with the production of antibodies, which are persistent throughout life. In the United States, about 30% of infants aged one year and 95% of five year olds have in the blood of antibodies to respiratory syncytial virus. Re-infection in infants, older children and adults with antibodies gives in most cases, slight upper respiratory tract infection in the form of a cold. In infants and young children infection treated with ribavirin, an antiviral agent with a wide spectrum of action. The use of this substance is severely restricted due to toxicity. There is, therefore, a great need for new therapeutic agent for the treatment of infections caused by RSWC.

In U.S. patent 5359131 described the stilbene sulfonic acid that block infection of cells with herpes simplex virus (HSV), human immunodeficiency virus (HIV) and cytomegalovirus (CMV).

The present invention relates to new anionic compounds containing a triazine ring, which have antiviral activity, and, in particular, activity against respiratory syncytial virus human (RSWC).

BRIEF DESCRIPTION OF THE INVENTION

The present and dstanley a radical, selected from the group including

< / BR>
< / BR>
< / BR>
C' is selected from-SO3H, -OSO3H, -OH or COOH;

In the' is-NH, NR1or 0;

R1selected from H, (C1-C6) lower alkyl straight or branched chain, where the carbon atoms may be optionally substituted by Cl, Br, F, OH or CN;

X is Cl, F or radical

< / BR>
U' is selected from the group comprising-SO2, -CO, -NC(O) or-NC (S);

W' is selected from the radicals:

< / BR>
Y represents -(CH2)n-;

n is 0-6;

m is 0-2;

Z is selected from H, CH3, CF3, -CH2-(halogen) where halogen is Cl, Br, F or I, -CH2OH, -COOH, -COO(C1-C6) lower alkyl straight or branched chain, -CONR2R2Joint VENTURE or

and

R2in each case, independently selected from H or (C1-C6) lower alkyl; or their pharmaceutically acceptable salts and esters.

It is understood that in cases where m=0, a five-membered rings are indicated as W'.

Pharmaceutically acceptable salts of the compounds of the present invention are those salts whose cations essentially are not toxic at the dose injected to achieve the desired effect, and do not have independent noticeable headlight is K; alkaline earth metals such as Ca or Mg; light metals of group IIIA including Al; and organic primary, secondary and tertiary amines and ammonium. Preferred are salts of sodium.

DETAILED DESCRIPTION OF THE INVENTION

Among the group of compounds defined by formula I, some of the subgroups of compounds are widely preferred. Widely preferred are such compounds or their pharmaceutically acceptable salts, where A represents the

< / BR>
Especially preferred are compounds where

C'=-SO3H, B'=-NH -, Y=-CH2-, Z=-CH2OH

Most preferred are compounds where

C'=-SO3H, B'=-NH -, Y=-CH2CH2-, Z=-CONH2< / BR>
Most highly preferred are compounds where A is

and C'=-SO3H, B=-NH -, Y=-CH2CH2-, Z=-CONH2< / BR>
The new compounds of the present invention can be obtained in accordance with the following schemes. Referring to Scheme 1, the condensation of 2, where A and b' above, with triazine having structure 3, where X is Cl, F or Br, at a temperature of about 0oC and pH from about 6.5 to about 7.2 gives intermediate compound 4. Subsequent reaction of compounds of formula 4 with joint pH of 6.5 to 7.2, followed by heating at 100-120oC and at a pH of 6.5 to 7.2 gives the desired products of formula I, above, are shown in schemes I and II as 1.

An alternative approach to compounds of formula I, as shown in Scheme II, the interaction triazine 3, where X is Cl, Br or F, with compounds 5, where' W' is specified above, at a temperature of from about -5 to about 5oC and pH 6.5 to 7.2, gives the condensation products 6. Interaction 6, where' W' indicated above and X is Cl, Br or F, 2 where A and b' are defined above, at a temperature of from about 45oC to about 55oC and pH from about 6.5 to about 7.2, followed by heating from about 100oC to about 120oC and pH 6.5 to 7.2, gives 1.

Stepwise condensation of the parent compounds 2, as shown in Scheme I, and 5, as shown in Scheme II, with triazine 3, where X is Cl, Br or F, which react similarly in water and in aqueous-organic media in the presence of appropriate bases, such as hydroxides, carbonates, phosphates or carbonates of sodium or potassium. Phosphate buffer at pH 7.0 is preferred.

The first stage of the condensation is carried out at a pH ranging from about 4 to about 8, preferably at a pH of from about 6.5 to about 7.2 and at temperatures from about -10oC wodnych triazine is in the same range of pH values and at a temperature of from about 10 to about 70oC, preferably at a temperature of from about 45 to about 55oC. Exchange of the third halogen atom derived from triazine is in the same range of pH values and temperatures ranging from about 80oC to about 150oC, preferably from about 100oC to 120oC.

The exchange of the second and third atoms of halogen from triazine derivatives of formula 6 (Scheme II) is carried out in organic medium in the presence of organic bases, such as trialkylamines, including triethylamine, diisopropylethylamine or N-(lower)alkylpiperidines.

The initial products for use in the total synthesis processes described in Schemes I and II are commercially available or can be synthesized in accordance with H. Adkins, E. F. Steinbring, E., Pickering. J. Amer. Chem. Soc., v. 46, p.1917(1924), G. C. Pat. N 1194388 (June 10, 1970) and U.S. patent N 5359131 (October 25, 1994). The initial compounds of Formula 2, where a' is oxygen, can be obtained from the substituted compounds of formula 2 (B'=-NH2as shown in Scheme III.

Primary aromatic amines 7, where A is given above, is subjected to the interaction with nitrous acid or other chemical reagents (for example, with an organic ester of nitrous acid) for diaset the crystals 9, containing phenolic groups.

According to Scheme IV, compounds (10) telenovela number can be converted into compounds (11) dibenzyline range in conditions of catalytic reduction (hydrogen - Pd/C) or in such circumstances, recovery, known in this area for the conversion of substituted stilbenoid compounds in dibenzyline connection. [Huang-Minlon, J. Amer. Chem. Soc. (1948) 70, 2802].

Compounds (12 and 13) of the formula I with Z=-COOH can be obtained by basic hydrolysis of the compound (14) at a pH of from 7.5 to 10.0, preferably of 8.0 to 8.5, and at a temperature of from 80 to 150oC, preferably from 100 to 120oC (Scheme V).

m-Aminobenzamide 17, where U' is-SO2or CO, Y, and Z are defined above, are synthesized according to Scheme VI.

The imides 15 is converted into m-nitrosulfonic 16 using suitable methods of amidation or tiliouine (T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Chemistry, JohnWiley & Sons, New York 1991, pp. 349-379). Nitro compounds 1B then restore up to 17 amino compounds by catalytic hydrogenation (hydrogen-Pd/C).

Pieperazinove derivatives 21, 22, where Z is-COOH or-CONH2are synthesized according to Scheme VII of the 3.5-piperidinecarboxylic acid eniu 20, either restored to a carboxyl-containing compound 21 or converted to carbamoylaspartate connection 22 by esterification or ammonolysis.

The present invention also includes methods of treating a mammal, preferably human, vaccination against viral infection, the methods comprising the administration to a mammal suffering from such infection, one or more compounds of the present invention and/or one or more pharmaceutically acceptable salts of the compounds. Viral infections, treatable using the compounds and methods of the present invention include infections that are respiratory syncytial virus human herpes simplex virus, human cytomegalovirus, and influenza virus, in particular, provironum influenza 3.

Compounds of the present invention can be administered to a needy mammal in any prescribed manner, including intranasal, oral, outdoor, transdermal, parenteral and intraperitoneally. It is clear that the treatment of a mammal, preferably human, will require different dosages of the active compounds and different modes of treatment in these individuals, dosage and mode must be determined appropriate by the attending physician. Effective antiviral amount of connections that need to be entered, you will usually be in the range of from about 0.5 mg/kg to about 500 mg/kg of body weight of the animal in the form of one or more dosages per day. The dosage is preferably given in the form of fractional doses two to four times a day or in a form that provides a slow release. For most large mammals the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of active compound in a homogeneous mixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be selected to provide the optimum therapeutic response. For example, several fractional doses may be administered daily or the dose may be proportionally reduced if it is shown the necessity of therapeutic situation. Compounds of the present invention can be administered with other antiviral agents or without them.

The present invention also includes pharmaceutical compositions which can be and the developments of the present invention or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers, diluents, fillers, binders, flavoring agents, and so forth. For oral administration, compositions containing the compounds of the present invention include solid or liquid compositions such as capsules, pills, pellets, pills, tablets, powders, syrups, solutions, suspensions and emulsions. Solid forms may be encapsulated in hard or soft gelatin capsules and may contain commonly used pharmaceutically various fillers, fibers, excipients, diluents, lubricants, disintegrating agents, suspendresume or stabilizing agents, and binding agents including, but not limited to, magnesium stearate, sodium lauryl sulfate, microcrystalline cellulose, polyvinylpyrrolidone, gelatin, alginic acid, Arabic gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, calcium phosphate, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch (such as starch from corn, potato or tapioca) and powdered sugar. Drugs may also include antioxidants, such as vitamin E, ascorbic acid, BHT and BHA. Such pharmaceutical is LEM, more often between about 5% and 60% by mass.

Suitable fillers for liquid oral preparations include diluents, such as water and alcohols, such as ethanol, benzyl alcohol, and the polyethylene alcohols, surface active substance, suspenders agent, or emulsifying agent, or without them. Dispersions can be prepared in glycerol, liquid polyethylene glycols or mixtures of the oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Compounds of the present invention can also be administered parenterally in the form of a dosage form for injection in a physiologically acceptable diluent, such as a sterile liquid or mixture thereof with water, including water, saline, aqueous dextrose and other pharmaceutically acceptable solutions of sugars, alcohols, such as ethanol, isopropanol or hexadecylamine alcohol, glycols, such as propylene glycol or polyethylene glycol, the ketals of glycerol, such as 2,2-dimethyl-1,3 - dioxolane-4-methanol, ethers, such as poly(ethylene glycol)400, pharmaceutically acceptable oil, fatty acid, ester of fatty acids or glycerides, or atsetilirovannye substances, such as a soap or a detergent, suspending agent such as pectin, carbomer, methylcellulose, hypromellose or carboxymethylcellulose, emulsifying agent or pharmaceutical excipients. In all cases, the form must be sterile and must be fluid to the extent to provide a slight gain in the syringe. It must be stable under the conditions of manufacture and storage and must be protected from the damaging action of microorganisms, such as bacteria and fungi.

Pharmaceutically acceptable oils that are suitable for use in the preparation include oils from petroleum, animal, vegetable or synthetic origin, including peanut oil, soybean oil, sesame oil, cottonseed oil, olive oil, sunflower oil, petrolatum and mineral oil. Fatty acids which can be used include oleic acid, stearic acid and isostearoyl acid, while suitable for use esters of fatty acids may include etiloleat and isopropylmyristate. Suitable Soaps include salts of fatty acids and alkali metal, ammonium and triethanolamine. Acceptable deterge acylaminoacyl, and anionic detergents, such as alkyl, aryl and reincorporate, alkyl, olefin, ether and monoglycerides, and sulfosuccinate. Suitable for use with non-ionic detergents may include oxides, fatty amines, alkanolamide fatty acids and polyoxyethylenesorbitan copolymers. Amphoteric detergents may include alkyl-beta-aminopropionic and Quaternary salts of 2-alkylimidazole, and mixtures thereof.

Parenteral compositions of the present invention preferably contain from about 0.5% to about 25% by weight of the active compounds described herein, in solution. Parenteral preparations in the form of sterile solutions or suspensions for injection will also preferably contain from about 0.05% to about 5% suspending agent in an isotonic medium. Can be added to the buffers and preservatives. Can also be added to the appropriate surfactant. These surfactants may include esters polietilensorbit fatty acids, such as servicemanual, and high molecular weight adducts of ethylene oxide with a hydrophobic base, obtained by condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions according to nantasenamat may include cutaneous application of the compounds of the present invention in the solvent system, designed to enhance the transdermal absorption, including ethanol or dimethyl - sulfoxide, with or without fillers. Preferably, these are considered external and transdermal compositions include adding compounds of the present invention in a bandage from the reservoir and porous membrane or in the plaster of a variety of solid matrices. Transdermal patches of this type are described in U.S. patents NN 3742951, 3797494, 3996934, 4031894, 4573996 and 4956171.

Intranasal drugs and medications according to the present invention can be administered in the form of nose drops or as an intranasal spray, such as an inhaler. The drugs may include any combination of pharmaceutically acceptable components, which are suitable for use in intranasal drug, including sterile water, saline solution, a stabilizing agent, such as polyethylene glycol having a molecular weight in the range from about 200 to 7500, or mixtures thereof.

Compounds of the present invention can be used for the treatment of viral infection or a prophylactic or therapeutic. For prophylactic use, the compounds can be introduced intranasally as a spray or in the form of exercises which should be the treatment will reflect the probability of infection with a specific viral agent and may depend on the epidemiological situation and risk factors faced by the patient. Connection introduced in this way, can be in various concentrations from 0.1 to 30 mg/ml, the resulting size varies from 0.1 to 1 ml/nostril. Alternatively, compounds may be introduced into the body by oral and intravenous dosing. For therapeutic use, the compounds can be administered topically to the lungs as an aerosol, or may be administered systemically by oral or intravenous dosing. This dosage can be administered during the period of time required to suppress viral infection.

Compounds of the present invention and obtaining them will become apparent with further non-limiting examples. Intermediate products of the reactions, the products and possible side products analyzed by thin-layer chromatography (TLC) on silica gel, using propane-2 - ol/ethyl acetate/4% ammonia in water (8:1:1, vol/vol) as solvent and high-performance liquid chromatography with reversed phase (HPLC - PF) [column: Vydac C18(4.6 mm x 25 cm), 5 mm; mobile art A-B-C (20:55:25, volume/volume) for 10 min] . Preparative HPLC OF is done on the system for gradient Rainin HPLC, using a Vydac preparative columns C18Peptide/Protein (10 mm, 22 mm x 25 cm); mobile phase: A: methanol/0.1 M ammoniated in water (pH 5.5) (1:4, vol/vol), B - methanol/acetonitrile (1:4, vol/vol); gradient: 18-32% B for 10 minutes.

Example 1

The disodium salt of 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2 - carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] - stilbene-2,2'-disulfonic acid

A solution of the acid chloride cyanuric acid (a 3.87 g, 21 mmol) in dioxane (25 ml) are added to phosphate buffer (100 ml, 0.3 M, pH 7) with stirring at a temperature of -3 -oC.

Then add a solution of 4,4'-diaminostilbene-2,2'- disulfonic acid (3,70 g, 10 mmol) in 1 N. NaOH (20 ml) over a 20 minute period and pH support at 6.5 to 7.2 by adding 1 N. NaOH. Stirring is continued for further 1 hour at the same temperature and pH, the reaction is controlled by the degree of completeness by analytical HPLC (yield 95%). Add a solution of 3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)sulfonylamino (13,20 g, 42 mmol) (Patent UK 1194388; July 10, 1970) in dimethyl sulfoxide (DMSO) (100 ml) for 20 minuten is the temperature, and then for 40 hours at 100-110oC, maintaining at pH of 6.6 to 7.2 by adding 1 N. NaOH. Once the reaction is completed, which is determined using an analytical HPLC (or TLC), the mixture is cooled to 20oC and acidified with 5,6 N. hydrochloric acid to pH 2. Add sodium chloride (60 ml, 4 M) and precipitated precipitated product is filtered, re-dissolved in minimum amount of water by adding 1 N. NaOH to pH 7 and re-planted by adding sodium chloride. The precipitation is filtered, washed with cold water (20 ml), propane-2-I (40 ml), acetone (60 ml) and dried in vacuum at 50oC. Yield of 13.0 g (72%); so pl. > 250oC, decomp. ; UV (water): 273 nm ( log 5,11), 350 nm ( log 4,89); MC(ES) (m/z): M-2887,9; MB 1821,2.

Example 2

The disodium salt of 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2 - carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] - stilbene-2,2'-disulfonic acid

A suspension of disodium salt of 4,4'-diaminostilbene-2,2'- disulfonic acid (1,21 g of 2.92 mmol) and 2-chloro-4,6-di [3-AMINOPHENYL-N,N-bis (2 - carbamoylethyl) sulfonylamino] -1,3,5-triazine (example 6) (4,47 g, 6,44 mmol) in sulfolane (70 ml) and diisopropylethylamine (1.5 ml) is heated in a sealed thin-walled glass tube to 115oC. Heating continued for 40 Cho 30oC add 1 N. NaOH (6.6 ml) and the product planted by adding propane-2-ol (200 ml). Fallen in the precipitate is filtered, washed with acetone (30 ml) and re-dissolved in a minimal volume of water and re-planted by adding ethanol. Loose residue after filtration was washed with ether (30 ml) and dried in vacuum at 50oC. Output 4,84 g (91%).

Example 3

The disodium salt of 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2 - carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] -stilbene-2,2' -disulfonic acid

Specified in the header of the get connection using the General conditions of example 1, where 2,4,6-Cryptor-1,3,5-triazine (304 mg, 2.25 mmol) interacts with 4,4'-diaminostilbene-2,2'-disulfonic acid (455 mg, 1.10 mmol) for 1 hour, and then with 3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)sulfonylamino (1.45 g, to 4.62 mmol) (Patent UK 1194388; June 10, 1970), with subsequent cleaning and getting the desired compound (1,21 g, 61%).

Compounds synthesized by the methods in examples 1-3 are identical, as shown HPLC, UV and mass spectra.

Example 4

The disodium salt of 4,4'-bis[4,6-di[3 - AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino]-1,3,5 - triazine-2-ylamino]-biphenyl-2,2'-disulphonate salt of 4,4'- diaminobiphenyl-2,2'-disulfonic acid (1,02 g, 2,62 mmol) and 2-chloro-4,6-di[3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)- sulfonylamino] -1,3,5-triazine (example 6) (4.26 deaths / g, USD 5.76 mmol) in 60 ml of DMSO-sulfolane (1:3, vol/vol) and diisopropylethylamine (1.2 ml). The product is obtained as colourless solids (3,90 g, 83%); so pl. >250oC, decomp.; UV (water): 272 nm (log 4,86); MC(ES) (m/z): M-2874,1; to 1,794 .2 MB.

Example 5

The disodium salt of 4,4'-bis[4,6-di[3-AMINOPHENYL-]-N,N-bis(2 - hydroxyethyl)sulfonylamino]-1,3,5-triazine-2-ylamino]- stilbene-2,2'-disulfonic acid

Specified in the header connection receive in accordance with the method used in the implementation example 2, using 4,4'-diaminostilbene-2,2'-disulfonate acid (28 mg, of 0.075 mmol) and 95 mg (0.15 mmol) of 2-chloro-4,6-di[3 - AMINOPHENYL-N,N-bis(3-hydroxyethyl)sulfonylamino]-1,3,5 - triazine (example 6) in sulfolane (20 ml) and diisopropylethylamine (35 ml) at 110oC for 18 hours. The cooled reaction mixture is mixed with deionized water (40 ml) and a solution of crude product purified by preparative HPLC-OFF. The fractions containing the desired product are pooled, the organic solvent is evaporated in vacuum (10 mm RT.CT.) when 30oC, and the product concentrate, absoluut and separated on octadecanol (C18) cartridge (900 mg, obtained otarola give 12 mg (11%) of the desired product; so pl. >250oC, decomp.; UV (water): 273 nm (log equal to 4.97); 350 nm (log 4,81); MC(ES) (m/z): M-2779,0; MB 1604,0.

Example 6

2-Chloro-4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)- sulfonylamino]-1,3,5-triazine

A solution of the acid chloride cyanuric acid (4,2 g, 22.7 mmol) in dioxane (55 ml) is added dropwise, with stirring, to a phosphate buffer (120 ml, 0.3 M, pH 7) and crushed ice (10 g) at a temperature of -2o- 0oC. To the resulting fine suspension is added dropwise over 30 minutes a solution of 3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)sulfonylamino (15.0 g, of 47.8 mmol) (Patent UK 1194388; June 10, 1970) in N,N-dimethylformamide (125 ml) and the pH of support at 6.5 to 7.2 by adding 1 N. NaOH. Stirring is continued for another 1 hour (0oC, pH 7.0) and the temperature raised to 55oC. Stirring is continued for 2.5 hours, the reaction is controlled by the degree of completeness by analytical HPLC (or TLC). Once the reaction is completed as determined by analytical HPLC (or TLC), the mixture is cooled to 0oC, add water (160 ml), and precipitated precipitated product is filtered, washed with cold water (50 ml), acetone (50 ml) and dried in vacuum at a temperature of 4 0oC. Yield 14.5 g (86%); so pl. &g is phenyl-N,N-bis(2-carbamoylethyl) sulfonylamino] -1,3,5-triazine-2-ylamino] -4'-[4-chloro-6- [3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5 - triazine-2-ylamino] stilbene-2,2'-disulfonic acid

A solution of the acid chloride cyanuric acid (205 mg, 1.12 mmol) in dioxane (1.5 ml) are added to phosphate buffer (10 ml, 0.3 M, pH 7) under stirring at a temperature of-3-0oC. Add a solution of disodium salt of 4,4'-diaminostilbene-2,2'-disulfonic acid (225 mg, 0.54 mmol) in phosphate buffer (3 ml), and maintain a pH of 6.5 to 7.2 by adding 1 N. NaOH. Stirring is continued for another 1 hour at the same temperature and pH, the reaction is controlled by the degree of completeness by analytical HPLC (yield 97%). Add a solution of 3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)- sulfonylamino (700 mg, of 2.23 mmol) in N,N-dimethylformamide (10 ml) for 10 minutes, and the temperature was raised to 60oC. Stirring is continued for 3 hours at the same temperature and for 20 hours at a temperature of 100-110oC, maintaining a pH of 6.6 to 7.2 by adding 1 N. NaOH. Once the reaction is completed, which is determined using an analytical HPLC (or TLC), the mixture is cooled to 20oC and acidified with 5,6 N. hydrochloric acid to pH 2, add sodium chloride (5 ml, 4 M) and precipitated precipitated product is filtered, washed with cold water (2 ml) and dried in vacuum at 40 ° oC. Two portions of a solution of the crude product (about 1 g) in deionized water (250 ml) PTS is practical solvents evaporated in vacuo (10 mm RT.article ) at a temperature of 30oC and the product concentrate, absoluut and separated on octadecanol (C18) cartridge (900 mg, obtained from Burdick &Jackson). The cartridge was washed with water (30 ml) and the product re-extragere methanol (50 ml). Evaporation of methanol leads to 268 mg (32%) of the desired product; so pl. >250oC, decomp. ; UV (water): 273 nm ( log a 4.83); 350 nm ( log of 4.44); MC(ES) (m/z): M-2749,15; MB 1544,3.

Example 8

The disodium salt of 4,4'-bis[4-chloro-6-[3-AMINOPHENYL-N, N-bis(2 - carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino]- stilbene-2,2'-disulfonic acid

A solution of the acid chloride cyanuric acid (0,91 g of 4.95 mmol) in dioxane (8 ml) are added to phosphate buffer (30 ml, 0.3 M pH 7) under stirring at a temperature of -3 - 0oC.

Add a solution of disodium salt of 4,4'-diaminostilbene - 2,2'-disulfonic acid (1,00 g, is 2.41 mmol) in deionized water (9 ml), and pH support at 6.5 to 7.2 by adding 1 N. NaOH. Stirring is continued for another 1 hour at the same temperature and pH, the reaction is controlled by the degree of completeness by analytical HPLC (yield 98%). Add a solution of 3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)- sulfonylamino (of 1.57 g, 5.0 mmol) in N,N-dimethylformamide (25 ml) for 10 minutes and the temperature p is a 2 by adding 1 to N. NaOH. Once the reaction is completed, which is determined using an analytical HPLC (or TLC), the mixture is cooled to 0oC and acidified with 5,6 N. hydrochloric acid to pH 2. Add sodium chloride (5 ml, 4 M) and precipitated precipitated product is filtered, washed with cold water (8 ml), acetone (20 ml) and ether (20 ml) and dried in vacuum at 40 ° oC. Yield 2.37 g (80%), so pl. > 300oC, decomp. ; UV (water): 273 nm ( log 4,57); 350 nm ( log 4,42); MC(ES) (m/z): M-2610,1; MB 1266,2.

Example 9

Disodium salt of 4-[4,6-di[3-AMINOPHENYL-N,N-bis(2-carbamoylethyl) sulfonylamino] -1,3,5-triazine-2-ylamino] -4'-[4-[3-AMINOPHENYL-N,N-bis (2-carbamoylethyl)sulfonylamino] -6-[3-AMINOPHENYL-N-(2-carbamoylethyl)- N'-(3-propionic acid)]-1,3,5-triazine-2-ylamino]stilbene-2,2' -disulfonic acid and

EXAMPLE 10

Disodium salt of 4-[4,6-di[3-AMINOPHENYL-N,N-bis(2 - carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] -4'-[4-[3- AMINOPHENYL-N-N-bis(2-carbamoylethyl)sulfonylamino] -6-[3 - AMINOPHENYL-N,N-bis(3-propionic acid)]-1,3,5-triazine-2 - ylamino]stilbene-2,2'-disulfonic acid

To a solution of compound of example 1 (200 mg, 0.11 mmol) in deionized water (20 ml) was added 1 N. NaOH (300 ml) and the mixture heated to boiling. The reaction mixture is left to warm up for 3 hours, the precipitated product is filtered, washed with cold water (2 ml) and dried in vacuum at 40 ° oC. a Solution of crude product (180 mg) in distilled water (125 ml) and purified by preparative HPLC-OFF. The fractions containing the desired product (example 9), combine the organic solvent is evaporated in vacuum (10 mm RT.CT.) at a temperature of 30oC and the product concentrate, absoluut and separated on octadecanol (C18) cartridge (900 mg, obtained from Burdick &Jackson). The cartridge was washed with water (30 ml) and the product re-extragere methanol (50 ml). Evaporation of the methanol give 24 mg (12%) of the desired product; so pl. >250oC, decomp.; UV (water): 273 nm ( 5,02); 350 nm ( log 4,76); MC(ES) (m/z): M-2888,3; MB 1822,6.

The second product (example 10) was isolated from the other fractions containing the desired compound (example 10) by HPLC-OF-separation, using the same methods for concentration, desalting and separation on octadecanol (C18) cartridge, as described in example 9. Yield 18 mg (9%), so pl. >250oC, decomp. ; UV (water): 273 nm ( log 4,92); 350 nm ( log 4,69); MC(ES) (m/z): M-2889,2; MB 1824,4.

Example 11

The disodium salt of 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2 - carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] - bibenzyl-2,2'-disulfonic acid

Solution the field of hydrogen for 5 days. The reaction mixture is filtered and the solvent is evaporated. The product is separated by preparative HPLC-OFF. The fractions containing the desired product are pooled, the organic solvent is evaporated in vacuum (10 mm RT. Art. ) at a temperature of 30oC and the product is separated on octadecanol (C18) cartridge (300 mg, obtained from Burdick &Jackson). The cartridge was washed with water (30 ml) and the product re-extragere methanol (50 ml). In the process of evaporation of the methanol remains 16 mg (50%) of the desired product; so pl. > 250oC, decomp.; UV (water): 274 nm ( log 4,96); MC(ES) (m/z): M-2889,2; MB 1824,4.

Example 12

The disodium salt of 4,4'-bis[4,6-di[4-AMINOPHENYL-N, N-bis(2 - carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] - stilbene-2,2'-disulfonic acid

Specified in the header connection receive in accordance with the method used in the synthesis example 2, using 4,4'-diaminostilbene-2,2'-disulfonate acid (48 mg, 0.125 mmol) and 2-chloro-4,6-di[4-AMINOPHENYL-N, N-bis(2 - carbamoylethyl)sulfonylamino] -1,3,5-triazine (example 18) (230 mg, 0,310 mmol) in dimethyl sulfoxide (12 ml) and diisopropylethylamine (260 ml). The product is obtained as colourless solid (173 mg, 77%); so pl. > 250oC, decomp. ; UV (water): 296 nm ( log 4,94); 352 nm ( log 4,57); MC(ES) (m/z): M-2883,2; MB 1822,4.

Mino] - diphenyl-2,2'-disulfonic acid

Specified in the header connection receive in accordance with the method used in the synthesis example 2, using the disodium salt of 4,4'-diaminobiphenyl-2,2'-disulfonic acid (113 mg, 0.33 mmol) and 2-chloro-4,6-di[4-AMINOPHENYL-N, N-bis (2-carbamoylethyl)sulfonylamino] -1,3,5-triazine (example 18) (535 mg, to 0.72 mmol) in 25 ml DMSO-sulfolane (2:3, vol/vol) and diisopropylethylamine (350 ml). The product is obtained as colourless solid (450 mg, 76%); so pl. > 250oC, decomp.; UV (water): 296 nm ( log 5,13); MC(ES) (m/z): M-2874,4; MB 1794,8.

Example 14

2-Chloro-4,6-di(3'-sultamicillin)-1,3,5-triazine

A solution of the acid chloride cyanuric acid (2.37 g, 12.9 mmol) in acetone (25 ml) is added dropwise, with stirring, to a phosphate buffer (60 ml, 0.3 M pH 7) at a temperature of-2-0oC. To the resulting fine suspension is added dropwise over 20 minutes a solution of m-sulfanilamide (4.35 g, to 25.3 mmol) in acetone (30 ml), and maintain the pH at 6.5 to 7.2 by adding 1 N. NaOH. Stirring is continued for further 30 minutes (0oC, pH 7.0) and the temperature raised to 55oC. Stirring is continued for 3 hours, the reaction is controlled by the degree of completeness with pomeschayut to 0oC, add water (100 ml), and precipitated precipitated product is filtered, washed with cold water (50 ml), dried on a filter and purified by dissolving in hot acetone (40 ml) and planted in benzene (150 ml). The product is filtered, washed with propan-2-I (20 ml) and ether (30 ml), dried in vacuum at a temperature of 30oC. Output and 3.72 g (64%); so pl. > 250oC, decomp; UV (MeOH): 277 nm ( log 4,68); MC(Cl) (m/z): MN 456,0.

Example 15

The disodium salt of 4,4'-bis[4,6-di[3-aminophenylacetamido] - 1,3,5-triazine-2-ylamino]stilbene-2,2'-disulfonic acid

Specified in the header connection receive in accordance with the method used to obtain the example 2, using the disodium salt of 4,4'-diaminostilbene-2,2'-disulfonic acid (216 mg, 0.52 mmol) and 2-chloro-4,6-di(3'-sultamicillin)-1,3,5 - triazine (example 14) (524 mg, 1.15 mmol) in sulfolane (15 ml) and diisopropylethylamine (250 ml) for 40 hours at a temperature of 115oC. After cooling to 20oC, the reaction mixture was diluted with ether (100 ml) and add 1 N. NaOH (2,08 ml). After centrifugation, the residue is stirred with propane-2-I (50 ml) up until crystallization is complete. The solid product is centrifuged, washed with methanol (2 x 30 ml) and ether (2 x 30 ml) and dried in vacuum at the pace of the BR>
The disodium salt of 4,4'-bis[4,6-di[3-aminophenylacetamido] - 1,3,5-triazine-2-ylamino]diphenyl-2,2'-disulfonic acid

Specified in the header connection receive in accordance with the method used to obtain the example 2, using 4,4'-diaminodiphenyl-2,2'-disulfonate acid (208 mg, of 0.60 mmol) and 2-chloro-4,6-di(3'-sultamicillin)-1,3,5-triazine (example 14) (607 mg, of 1.33 mmol) in sulfolane (20 ml) and diisopropylethylamine (850 ml) for 40 hours at a temperature of 115oC. After cooling to 20oC, the reaction mixture was diluted with ether (150 ml) and add 1 N. NaOH (2,40 ml). After centrifugation, the residue is stirred with propane-2-I (50 ml) up until crystallization is complete. The solid product is centrifuged, washed with methanol (40 ml) and ether (2 x 20 ml) and dried in vacuum at a temperature of 30oC. Output (505 mg, 72%); so pl. > 250oC, decomp.; UV (water): 276 nm ( log 4,93).

Example 17

4,4'-Dihydroxydiphenyl-2,2'-disulfonate acid

To a suspension of 4,4'-diaminodiphenyl-2,2'-disulfonic acid (of 4.44 mg, 12.9 mmol) in water (20 ml) add a solution of sodium carbonate (8.6 ml, 1.5 M) by heating until then, until you get a clear solution. After cooling to 5oC to this solution add a solution of the Institute to a solution of concentrated sulfuric acid (3.8 ml) in water (13 ml) and crushed ice (10 g) at a temperature of -5 - -2oC. Stirring is continued for further 30 minutes, and the reaction mixture is heated to 65oC. This temperature is maintained until until the ongoing evolution of nitrogen. The mixture is cooled to 10oC and neutralized with dry sodium carbonate and the solution is evaporated to a residue. The residue is dried in vacuum at a temperature of 50oC, is mixed with ethanol (225 ml) and filtered. The filtrate is evaporated and dried in vacuum at 40 ° oC. Output 3,88 (87%); so pl. > 250oC, decomp. ; UV (0,05 N. NaOH): 252 nm ( log 4,16), 311 nm ( log 3,40); MC(ES) (m/z): (M-H)-1345,0; MB 346,0.

Example 18

2-Chloro-4,6-di[4-AMINOPHENYL-N, N-bis(2-carbamoylethyl)- sulfonylamino]-1,3,5-triazine

Specified in the header of the connection receives the method to be used when getting in example 6 using 4-AMINOPHENYL - N,N-bis(carbamoylethyl)sulfonylamino (3,3 g, 10.5 mmol) (Patent UK 1194388; June 10, 1970) and the acid chloride cyanuric acid (1.0 g, 5.4 mmol). The product is obtained as a colourless solid (3.5 g, 88%); so pl. > 250oC, decomp. ; UV (DMSO): 303 nm ( log 4,84); MC(Cl) (m/z): MH 740,1.

Example 19

The disodium salt of 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2 - carbamoylethyl)sulfonylamino]-1,3,5-triazine-2-yloxy]- diphenyl-2,2'-disulfonic acid

N,N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5 - triazine (Example 6) (550 mg, to 0.74 mmol) in sulfolane-N, N - dimethylformamide (15 ml, 2:1 volume/volume) and NaOH (1 N., of 1.48 ml) was heated in a sealed thin-walled glass tube to 115oC. Heating continued for 50 hours. Once the reaction is completed, which is determined using an analytical HPLC (or TLC), the mixture is cooled to 20oC and the product are planted by adding propane-2-ol (70 ml), washed on the filter with cold ethanol (15 ml) and dried in vacuum at 40 ° oC. Two portions of a solution of the crude product (about 0.6 g) in deionized water (200 ml) is treated separately by preparative HPLC-OFF. The fractions containing the desired product are pooled, the organic solvent is evaporated in vacuum (10 mm RT.CT.) at a temperature of 30oC, and the product concentrate, absoluut and separated on octadecanol (C18) cartridge (900 mg, obtained from Burdick &Jackson). The cartridge was washed with water (30 ml) and the product re-extragere methanol (50 ml). In the process of evaporation of the methanol remains 171 mg (28%) of the desired product; so pl. > 250oC, decomp.; UV (water): 272 nm ( log 4,86); MC(ES) (m/z): M-2875,2; MB 1796,4.

Example 20

The disodium salt of 5,5'-dimethyl-4,4 bis[4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] diphenyl-2,2'-disulf imanae the disodium salt of 5,5'-dimethyl-4,4' -diaminodiphenyl-2,2'-disulfonic acid (206 mg, 0.49 mmol) and 2-chloro-4,6-di[3'-AMINOPHENYL)-N, N-bis(2-carbamoylethyl) sulfonylamino]-1,3,5-triazine (example 6) (805 mg, of 1.08 mmol) in 30 ml of DMSO-sulfolane (1:1, volume/volume) and diisopropylethylamine (200 ml) for 50 hours at a temperature of 115oC. the Product after HPLC-purification obtained as colourless solid (191 mg, 22%); so pl. > 250oC, decomp.; UV (water): 274 nm ( log 5,08); MC(ES) (m/z): M-28883,3; MB 1822,6.

Example 21

2-Chloro-4,6-di[3-AMINOPHENYL-N, N-bis(3-hydroxyethyl)- sulfonylamino] -1,3,5-triazine

A solution of the acid chloride cyanuric acid (135 mg, 0.73 mmol) in dioxane (55 ml) is added dropwise with stirring to a phosphate buffer (120 ml, 0.3 M, pH 7) and crushed ice (10 mg) at a temperature of from -2 to 0oC. To the resulting fine suspension is added dropwise over 20 minutes a solution of 3-AMINOPHENYL-N,N-bis(2-hydroxyethyl)sulfonylamino (365 mg, of 1.40 mmol) in N, N-dimethylformamide (125 ml) and maintain a pH of 6.5 to 7.2 by adding 1 N. NaOH. Stirring is continued for another 1 hour (0oC, pH 7.0) and the temperature was raised to 55oC. Stirring is continued for 2.5 hours, the reaction is controlled by the degree of completeness by analytical HPLC (or TLC). As soon as the reaction severalspecies precipitated product is filtered, washed with cold water (50 ml), acetone (50 ml) and dried in vacuum at 40 ° oC. Yield 395 mg (89%), so pl. > 250oC, decomp.; UV (DMSO): 284 nm.

Example 22

The disodium salt of 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2 - hydroxyethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] - diphenyl-2,2'-disulfonic acid

Connection receive in accordance with the method used to obtain the example 2, using 4,4'-diaminodiphenyl-2,2'-disulfonate acid (28 mg, 0.08 mmol) and 115 mg (0,17 mmol) of 2-chloro-4,6-di[3-AMINOPHENYL)- N, N-bis(3-hydroxyethyl)sulfonylamino]-1,3,5-triazine (example 21) in sulfolane (10 ml) and diisopropylethylamine (25 ml) at a temperature of 110oC for 18 hours. The product after HPLC-purification obtained as a colorless solid (16 mg, 13%); so pl. > 250oC, decomp.; UV (water): 272 nm ( log 4,88); MC(ES) (m/g): M-2776,0; MB 1534,0.

Example 23

The disodium salt of 9,9-dioxo-2,7-bis[4,6-di[3-AMINOPHENYL-N,N - bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] -dibenzothiophen-3,6-disulfonic acid

Specified in the header connection receive in accordance with the method used in the preparation of example 1, applying a solution of the acid chloride cyanuric acid (59 mg, 0.32 mmol), 9,9-dioxo-2,7-deliverymen]-1,3,5-triazine (example 6) (300 mg, 0.96 mmol) in dioxane (15 ml) and phosphate buffer (20 ml, 0.3 M, pH 7) at a temperature of 110oC for 18 hours. The product after HPLC-purification obtained as a colorless solid (64 mg, 11%); so pl. > 250oC, decomp. ; MC(ES) (m/z): M-2905,1; MB 1858,2.

Example 24

The disodium salt of 4,4'-bis[4-chloro-6-di[4-amino-N' -[3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)sulfonylamino] benzamide] -1,3,5-triazine-2-ylamino]stilbene-2,2'-disulfonic acid

Connection receive in accordance with the method used to obtain the example 2, using 4,4'-diaminostilbene-2,2'-disulfonate acid (20 mg, 0,054 mmol) and 112 mg (0.12 mmol) of 2,4-dichloro-6- [4-amino-N'-[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl) sulfonylamino] benzamid-1,3,5-triazine (example 26) in sulfolane (20 ml) and diisopropylethylamine (38 ml) at a temperature of 110oC for 18 hours. The product after HPLC-purification obtained as a colorless solid (20 mg, 23%); so pl. > 250oC, decomp.; UV (water): 295 nm (log 4,54), 354 (log 4,39); MC(ES) (m/z): M-2727,1; MB 1482,2.

Example 25

The disodium salt of 4,4'-bis[4,6-di[4-amino-N'-[3-AMINOPHENYL-N, N-bis(2-hydroxyethyl)sulfonylamino] benzosulfimide] - 1,3, 5-triazine-2-ylamino] stilbene-2,2'-disulfonic acid

Specified in the header of the connection p is Sultonova acid (20 mg, 0,054 mmol) and 203 mg (0.22 mmol) of 2-chloro-4,6-di[4-amino-N'- [3-AMINOPHENYL-N,N-bis(2-hydroxyethyl)sulfonylamino] -benzosulfimide] -1,3,5-triazine (example 27) in sulfolane (20 ml) and diisopropylethylamine (38 ml) at a temperature of 110oC for 18 hours. The product after HPLC-purification obtained as a colorless solid (30 mg, 25%); so pl. > 250oC, decomp. ; UV (water): 295 nm ( log to 5.21), 350 ( log 4,69); MC(ES) (m/z): M-21089,3; MB 2226,6.

Example 26

2,4-Dichloro-6-[4-amino-N'-[3-AMINOPHENYL-N,N-bis(2 - carbamoylethyl)sulfonylamino]benzamide]-1,3,5-triazine

A solution of the acid chloride cyanuric acid (56 mg, 0.3 mmol) in dioxane is added with stirring to a phosphate buffer (12 ml, 0.3 M, pH 7) at a temperature of -2oC. To the resulting suspension is added dropwise a solution of 4-amino-N'-[3-AMINOPHENYL-N, N - bis(2-carbamoylethyl)sulfonylamino] benzamide (130 mg, 0.3 mmol) in N,N-dimethylformamide (2 ml), and maintain a pH of 6.5 to 7.2 by adding 1 N. NaOH. Stirring is continued for another 1 hour (0oC, pH 7.0), then add water (20 ml) and precipitated precipitated product is filtered, washed with cold water (10 ml), acetone (5 ml) and dried in vacuum at a temperature of 20oC to obtain 108 mg (62%) of the desired product; so pl. >250oC, decomp.; UV (DMSO): 285 nm.


Specified in the header connection receive in accordance with the method used in obtaining in example 6 using 4 - amino-N'-[3-hydroxyethyl)sulfonylamino] benzosulfimide (125 mg, 0.31 mmol) and acid chloride cyanuric acid (28 mg, 0.15 mmol). The product is obtained as a colourless solid (105 mg, 74%); so pl. > 250oC, decomp.; UV (DMSO): 298 nm.

Example 28

4,4'-Dinitro-2,2'-diphenyl acid

2,2'-Diphenyl acid (Aldrich, 50.0 g, 206 mmol) in parts add to 500 ml of 3:1 90% HNO3/H2SO4maintaining the temperature not exceeding 10oC. a Clear solution is stirred in an ice bath for one hour, then carefully quenched with approximately 750 g of ice. White solid product, which shows the ratio of isomers as 2:1, is separated by vacuum filtration. This mixture is purified using chromatography, passing through 1.5 kg of silica gel, suspended in 8:2 isopropanol/ammonium hydroxide and elwira with the same mixture of solvents. The product comes out of the column first, almost going out with the front of the solvents. Side isomer comes out of the speakers later (see P. R. 232-11). Fraction of the product are concentrated on a rotary evaporator. A concentrated solution of popcicle d, J=8,7); to 8.45 (1H, DD, J=2.5 a, 8,7); 8,68 (1H, d, J= 2,5). 13 (1H, user with). CHN: Theory: C: 48,60%; H: 2,77%; N: 8,10%. theoretically calculated from 0.75 the moles of water. Found: C: 48,68%; H: 2,72%; N: 7,42%.

Example 29

4,4'-Diamino-2,2'-diphenyl acid 4,4'-Dinitro-2,2'-diphenyl acid (Example 28, 10.0 g, to 30.1 mmol; P. R. 232-9) is suspended in 90 ml of water and titrated to pH 7 with saturated NaHCO3(can be used NaOH). Add 10% Pd/C (0.5 g; Aldrich) and the mixture restore at a pressure of 30 lb/inch2within one hour. The catalyst is removed by filtration and the filtrate concentrated to ~ 20 ml Cautiously add acetone (40 ml) to the concentrated solution, causing precipitation of the product in the form of a disodium salt. It is collected by vacuum filtration and dried in vacuum, obtaining 9 g of 4,4'-diamino-2,2'-diphenyl acid disodium salt. 300 MHz NMR (D2O): 4,70 (-NH2with); of 6.71 (1H, DD, J=2,4, 8,25); 6,79 (1H, d, J=2,4); 7,00 (1H, d, J=8,25). Theoretically: C: 49,64%; H: 3.72 per cent; N: 8.27 per cent (Calculated from 1.25 the moles of water). Found: C: 49,55%; H: 3.72 Per Cent; N: Of 7.90%.

Example 30

The disodium salt of 4,4'-bis (4,6-bis{3-[bis-(2 - carbamoylethyl)-sulfamoyl] phenylamino}-1,3,5-triazine-2 - ylamino]diphenyl-2,2'-dicarboxylic acid

A suspension of disodium salt of 4,4'-diaminodiphenylamine acid (Example 29, 66 mg, 0,19 mmol what falana (10 ml) and diisopropylethylamine (0.3 ml) is heated in a sealed thin-walled glass tube to 115oC. Heating continued for 50 hours. Once the reaction is completed, which is determined using an analytical HPLC (or TLC), the mixture is cooled to 20oC, and the product is planted by adding propane-2-ol (70 ml), washed on the filter with cold ethanol (15 ml) and dried in vacuum at 40 ° oC. Two parts of a solution of the crude product (about 0.3 g) in deionized water (200 ml) is treated separately by preparative HPLC-OFF. The fractions containing the desired product are pooled, the organic solvent is evaporated in vacuum (10 mm RT.CT.) at a temperature of 30oC and the product concentrate, absoluut and separated on octadecanol (C18) cartridge (900 mg, obtained from Burdick &Jackson). The cartridge was washed with water (20 ml) and the product re-extracted with methanol (40 ml). In the process of evaporation of the methanol remains 112 mg (34%) of the desired product; so pl. > 250oC, decomp.; MC(ES) (m/z): M-2840,2; MB 1724,4.

Example 31

3-AMINOPHENYL-N,N-bis(2-methoxycarbonylethyl)sulfonylamino

3-Aminobenzenesulfonamide (3 g, of 17.4 mmol) dissolved in nitrobenzene (55 ml) at a temperature of 100oC. Then the temperature is reduced to 90oC and add methyl acrylate (5 ml, of 55.5 mmol) and Triton B (0.4 ml, 40% in MeOH). The reaction vessel supply silly. Add a solution of HCl (30 ml, 1M in diethyl ether) to the reaction mixture, getting sticky oil. It is dissolved in 50% ethyl acetate/hexane and loaded into a column filled with silica gel. The desired product elute with hexane. The solvent is evaporated to obtain 3.9 g (65%) of the desired product; (m/z): MH 343,2, so pl. 59-60oC.

Example 32

3-AMINOPHENYL-N,N-bis(2-methylcarbonate)sulfonylamino

To a solution of methylamine (10 ml, 8,03 M, 33% in ethanol) is added a solution of 3-AMINOPHENYL-N,N-bis(2-methoxycarbonylethyl)sulfonylamino (Example 31, 0.5 g of 1.45 mmol) in ethanol (10 ml), stirring at room temperature. After 24 hours, TLC shows completion of the reaction. To the reaction mixture, water is added and the compound is extracted with chloroform and dried over sodium sulfate (50 mg). The output is 300 mg (60%)%; MC(ES) (m/z) 345,2 (M+H)+< / BR>
Example 33

3-[[3-(4-{ 3-[Bis-(2-methylcarbamoylmethyl)sulfamoyl] -phenylamino} -6-chloro-[1,3,5]triazine-2-ylamino)benzazolyl]- (2-methylcarbamoylmethyl)amino] -N-methylpropionamide

To phosphate buffer (15 ml, pH 7) at a temperature of 0oC add a solution of the acid chloride cyanuric acid (550 mg, 2,98 mmol) in dioxane (4 ml). To the mixture that has the color and consistency of milk, add a solution of 3-AMINOPHENYL-N, N-bis(2 - metalchem add 1 to N. the sodium hydroxide solution. After addition the temperature was raised to 55oC for 2 hours, at this point, the analysis using HPLC indicates complete reaction. The mixture was diluted with water (100 ml), saturated with sodium chloride and extracted with ethyl acetate (4 x 150 ml). Concentrate the combined extracts to a viscous oil (3.5 g), which is treated with acetonitrile (30 ml) and left overnight in the refrigerator. Resinous precipitated residue is stirred with ether (20 ml) up until all the sludge will turn into a fine powder, which is separated by filtration. Get a solid amber color (1.8 g, yield 78%); so pl. > 250oC, decomp.; MC(ES) (m/z) 795,7 (M+H)+< / BR>
Example 34

The disodium salt of 4,4'-bis-[[4,6-bis[[3-[[bis-[3-(methylamino)- 3-oxopropyl] amino] sulfonyl] phenyl]amino]-1,3,5-triazine-2-yl]amino] [1,1'-diphenyl]-2,2'-disulfonic acid

The mixture 3-[[3-(4-{ 3-[bis-(2-methylcarbamoylmethyl)sulfamoyl] phenylamino}-6-chloro-[1,3,5] triazine-2-ylamino)benzazolyl] -(2-methylcarbamoylmethyl)amino] -N-methylpropionamide (Example 33, 200 mg, 0.25 mmol), disodium salt of 4,4'-diaminodiphenyl - 2,2'-disulfonic acid (41 mg, 0.11 mmol) and diisopropylethylamine (50 ml, 0.28 mmol) in dimethyl sulfoxide (4 ml) heated in a sealed property product (40 mg, 19%); so pl. > 250oC, decomp.; MC(ES) (m/z) 930,5 (M-2); MB 1908,1.

Example 35

The disodium salt of 4,4'-bis-(4,6-bis-{ 3-[bis-(2 - methylcarbamoylmethyl)sulfamoyl] phenylamino}-[1,3,5]triazine-2 - ylamino)diphenyl]-2,2'-dicarboxylic acid

To a solution of 3-[[3-(4-{3-[bis-(2-methylcarbamoylmethyl)-sulfamoyl] phenylamino} -6-chloro-[1,3,5] triazine-2-ylamino)-benzazolyl]- (2-methylcarbamoylmethyl)amino] -N-methylpropionamide (Example 33, 200 mg, 0.25 mmol), add the disodium salt of 4,4' -diaminodiphenyl-2,2'-dicarboxylic acid (37 mg, 0.12 mmol) in dimethyl sulfoxide (4 ml), the solution (37 mg, 0.12 mmol) in phosphate buffer (3 ml, pH 7). The mixture is heated at a temperature of 110oC for 24 hours. After cooling, add water (100 ml) and the mixture is separated on a preparative HPLC column. Yield 60 mg (27%) of white solid product; so pl. > 250oC, decomp.; MC(ES) (m/z) 894,5 (M-2); MB 1836,0.

Example 36

Dimethyl ether of 4,4'-bis-(4,6-bis-{3-[bis-(2-carbamoylethyl) sulfamoyl] phenylamino}-[1,3,5]triazine-2-ylamino)diphenyl] -2,2'-dicarboxylic acid

A mixture of 2-chloro-4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl) sulfonylamino] -1,3,5-triazine (Example 6, 200 mg, 0.27 mmol), dimethyl ether24,4'-diamino-2,2'-diphenyl acid (38 mg, 0.13 mmol) and diisopropylethylamine (55 ml, 0,31 t (50 ml). The precipitation is filtered, washed with isopropyl alcohol. The dry solid product (190 mg) purified by HPLC to obtain a white solid product (53 mg, 24% yield); so pl. > 250oC, decomp.; MC(ES) (m/z) 854,8 (M+2H)2+; MB 1707,8.

Example 37

3-Nitrophenyl-N,N-bis(2-hydroxypropyl)sulfonylamino

To a stirred solution of diisopropanolamine (50.0 g, 75 mmol) in water (500 ml) is added m-nitrobenzenesulfonate (57,1 g, 35 mmol). The mixture is vigorously stirred for 25 hours at room temperature. The resulting suspension is filtered, the solid product is washed with H2O (2 x 400 ml), dried and re-crystallized from a mixture of ethyl acetate/hexanol to give the desired product as white crystals. The output is 65.8 g (88%); so pl. 114-116oC;1H NMR (CDCl3, 300 MHz) 8,67 (d, J=5,1 Hz, 1H), 8,44 (d, 1H), 8,15 (d, J=6.0 Hz, 1H), to 7.77 (m, 1H), 4,78 (s, 2H), 4,18 (m, 2H), 3,10 (d, J=5,9 Hz, 4H), of 1.16 (DD, 6H); MC(ES) (m/z) 319,5 (M+H)+< / BR>
Example 38

3-AMINOPHENYL-N,N-bis(2-hydroxypropyl)sulfonylamino

A solution of 3-nitrophenyl-N, N-bis(2-hydroxypropyl) sulfonylamino (Example 37, 10.0 g, of 31.4 mmol) in methanol (100 ml) hydronaut over palladium catalyst (10% Pd/C, 1 g) for 1.5 hours. The resulting mixture is filtered through a layer of Celine, elwira a mixture of ethyl acetate/hexane 4:1. The desired product is obtained in the form of pale yellow crystals. The output is 8.2 g (90,5%); NMR (CDCl3, 300 MHz) 7,28 (d, 1H), 7,13 (m, 1H), to 7.09 (m, 1H), 6,86 (d, 1H), 4,20 (m, 1H), 4,13 (DD, 1H), 3,37 (DD, 1H), to 3.02 (d, 2H), 2,80 (DD, 1H), 1,16 (DD, 6H); MC(ES) (m/z) 289,5 (M+H)+< / BR>
Example 39

2-Chloro-4,6-bis-{ 3-[bis-(2-hydroxypropyl)sulfamoyl] - phenylamino} -[1,3,5]-triazine

Specified in the header connection receive in accordance with the method of example 33, using the acid chloride cyanuric acid (160 mg, 0.87 mmol), 3-AMINOPHENYL-N, N-bis(2-hydroxypropyl)sulfonylamino (700 mg, 2.0 mmol), dioxane (3 ml), phosphate buffer (10 ml, 0.3 M, pH 7), N,N-dimethylformamide (5 ml) and 1 N. NaOH. The product is dropped off from the cooled reaction mixture with water in the form of amber-yellow viscous oil, centrifuged, washed with water and dried in high vacuum to obtain 640 mg (93%) chlorotriazine. so pl. > 250oC, decomp.; MC(ES) (m/z) 687,7, 689,7 (M+H)+< / BR>
Example 40

The disodium salt of 4,4'-bis-(4,6-bis-{ 3-[bis-(2-hydroxypropyl) sulfamoyl] phenylamino} -[1,3,5] -triazine-2-ylamino)diphenyl] -2,2'- disulfonic acid

A mixture of 2-chloro-4,6-bis-{ 3-[bis-(2-hydroxypropyl) sulfamoyl]phenylamino} -1,3,5-triazine (Example 39, 300 mg, 0.44 mmol), disodium salt of 4,4'-diaminodiphenyl-2,2'-disulfonate dovy mode) at a temperature of 110oC for 2 hours. After cooling the reaction mixture without extract is subjected to preparative HPLC in the system water/acetonitrile at YMC Prodigy polymeric C18 column. The product is obtained as colorless solid (170 mg, 50.2 per cent); so pl. > 250oC, decomp.; MC(ES) (m/z) 822,3 (M-2H)2-; MB 1691,9 (MB+2Na).

Example 41

The disodium salt of 4,4'-bis-(4,6-bis-{ 3-[bis-(2-hydroxypropyl) sulfamoyl]phenylamino}-[1,3,5]-triazine-2-ylamino)diphenyl]-2,2' -dicarboxylic acid

A mixture of 2-chloro-4,6-bis-{ 3-[bis-(2-hydroxypropyl)sulfamoyl] phenylamino} -1,3,5-triazine (Example 39, 178 mg, 0.25 mmol), dihydrochloride 4,4'-diamino-2,2'-diphenyl acid (35 mg, 0.11 mmol), 3 ml of DMSO, 0.5 ml of phosphate buffer (1 N., pH 7) and 0.5 ml of 1 N. NaOH is heated in a furnace in a sealed tube for 18 hours, then without removing subjected to preparative HPLC to obtain 90 mg (50.5 per cent) of the desired product. So pl. > 250oC, decomp.; MC(ES) (t/g) 788,1 (M+2H)2+; MB 1619,8 (MB+2Na).

Example 42

2-Chloro-4,6-bis-(3-[bis-carbamoylmethyl-1-sulfamoyl]-phenylamino} -[1,3,5] -triazine

Specified in the header connection receive in accordance with the method of example 33, using the acid chloride cyanuric acid (0,42 g of 2.27 mmol), 3-AMINOPHENYL-N, N-bis - carbamoyltransferase (CL 55675, which is heterogeneous during the entire procedure. The resulting pink precipitate is centrifuged, washed several times with water, re-dissolved in minimum amount of DMF and re-planted with water. Final separation and dried to give 0.7 g (45,1%) of the desired product; so pl. > 250oC, decomp.; MC(ES) (m/z) 683,7, 685,7 (M+H)+< / BR>
Example 43

Disodium salt of 4',4-bis-{4,6-bis-[3-[bis-carbamoylmethyl-1 - sulfamoyl] phenylamino]-[1,3,5]-triazine-2-ylamino}diphenyl-2,2' -disulfonic acid

Specified in the header connection receive in accordance with the method of example 40, using 2 - chloro-4,6-bis-{3-[bis-(carbamoylmethyl-1-sulfamoyl] phenylamino} -[1, 3,5] triazine (Example 42, 500 mg, 0.73 mmol), disodium salt of 4,4'-diaminodiphenyl-2,2'-disulfonic acid (114 mg, 0.29 mmol), 2.5 ml of DMSO, 2.5 ml phosphate buffer (1 N., pH 7) and 1.0 ml of 1 N. NaOH. Microwave heating (PROLABO single-mode) continued for 1 h at a temperature of 105oC. the resulting mixture is subjected to preparative HPLC, which gives 50 mg (10,2%) of product as a pink solid product; so pl. > 250oC, decomp.; MC(ES) (m/z) 818,2 (M-2H)2-; MB 1683,7 (MB+2Na).

Example 44

Disodium salt of 4',4-bis-{4,6-bis-[3-[bis-carbamoylmethyl-1 - sulfamoyl)phenylamino]-[1,3,5]-triazine-2-ylamino}diphenyl-2,2' -dicarboxylic acid

Indicated is carbamoylmethyl-1-sulfamoyl] phenylamino} -[1,3,5] -triazine (Example 42, 500 mg, 0.73 mmol), dihydrochloride 4,4'-diamino - 2,2'-diphenyl acid (100 mg, 0.29 mmol), 2.5 ml of DMSO, 2.5 ml phosphate buffer (1 N., pH 7) and 1.0 ml of 1 N. NaOH. Microwave heating (PROLABO single-mode) is continued for 1 hour at a temperature of 105oC. the resulting mixture is subjected to preparative HPLC, which gives 20 mg (4,3%) of product as a pink solid; T. pl. > 250oC, decomp.; MC(ES) (m/z) 784,0 (M+2H)2+; MB 1619,8 (MB+2Na).

Example 45

1-(3-Nitrobenzenesulfonyl)piperidine-3,5-dicarboxylic acid

A solution of 3,5-pyridinedicarboxylic acid (3,34 g, 20 mmol) in 50 ml of water and 10 ml of concentrated ameriglide hydronaut in a Parr apparatus at a pressure of 22 feet/inch2over 1 g of ruthenium catalyst (5% ruthenium on the powder of aluminum oxide) within 48 hours. After filtration of the catalyst and removal of solvent the crude 3,5-piperidinylcarbonyl acid dissolved in 60 ml of 1 N. NaOH and heated with 6.6 g (30 mmol) of m-nitrobenzenesulfonamide. The reaction mixture was stirred at room temperature and maintain the pH to 9.5 by adding 1 N. NaOH until then, until there is no further precipitation. The reaction mixture is stirred for another 1.5 hours, the precipitate is filtered, and the filtrate acidified with is during the night with the receipt of 5.3 g (74%) of the desired product.1H NMR (DMSO-d6, 300 MHz) 8,55 (d, 1H), 8,40 (s, 1H), 8,15 (d, 1H), 7,95 (t, 1H), 3,14 (m, 4H), of 1.65 (m, 2H), 1,45 (m, 2H); MC(ES) m/z 359 (M+H)+< / BR>
Example 46

Dimethyl ether 1-(3-nitrobenzenesulfonyl)piperidine-3,5 - dicarboxylic acid

A suspension of 1-(3-nitrobenzenesulfonyl)piperidine-3, 5-dicarboxylic acid (Example 45, 3.6 g, 10 mmol) in THF (200 ml) is treated at a temperature of 0oC excess diazomethane and stirred at this temperature until such time as the suspension becomes a clear bright yellow solution. The reaction mixture is heated at room temperature, filtered, evaporated and purified by column chromatography on silica gel to obtain 2.5 g (64%) of colorless crystals of the desired product.1H NMR (CDCl3, 300 MHz) 8,65 (s, 1H), 8,49 (d, 1H), 8,11 (d, 1H), 7,81 (t, 1H), of 3.73 (s, 6H), 3,40 (m, 4H), 2.95 and (m, 2H), 2.05 is (t, 2H); MC(ES) m/z 387,2 (M+H)+< / BR>
Example 47

Diamid 1-(3-nitrobenzenesulfonyl)piperidine-3,5-dicarboxylic acid

A solution of dimethyl 1-(3-nitrobenzenesulfonyl)- piperidine-3,5-dicarboxylic acid (Example 46, 2.5 g, 6.5 mmol) in 200 ml of methanol saturated with ammonia at a temperature ofoC, seal and leave at room temperature for 7 days. The resulting yellow solution was concentrated until the volume of the bottom-cream crystals. MC(ES) m/z 357,1 (M+H)+< / BR>
Example 48

1-(3-Aminobenzenesulphonyl) piperidine-3,5-dicarboxylic acid

A solution of 1-(3-nitrobenzenesulfonyl)piperidine-3,5-dicarboxylic acid (Example 45, 2.5 g, 4.2 mmol) in 150 ml of methanol hydronaut in a Parr apparatus at a pressure of 25 lb/in2above 0.15 g of palladium catalyst (10% palladium on coal) for 1 hour. Filtration of the catalyst and removal of solvent gives 1.8 g (79%) of the desired product as a white solid product. MC(ES) m/z 329,1 (M+H)+< / BR>
Example 49

Diamid 1-(3-aminobenzenesulphonyl)piperidine-3,5-dicarboxylic acid

The solution diamide 1-(3-nitrobenzenesulfonyl) piperidine-3,5-dicarboxylic acid (Example 47, 1.5 g, 4.2 mmol) in 300 ml of methanol hydronaut in a Parr apparatus at a pressure of 25 lb/in2over 0.1 g of palladium catalyst (10% palladium on coal) for 1.5 hours. Filtration of the catalyst and removal of solvent gives 1.26 g (92%) of the desired product as a light grey solid product. MC(ES) m/z 327,1 (M+H)+< / BR>
Example 50

2-Chloro-4,6-bis-[3-(3,5-dicarbonitrile-1-sulfonyl) -phenylamino]-[1,3,5]-triazine

A solution of the acid chloride cyanuric acid (280 mg, 1.5 mmol) in dioxane (5 ml) is added under stirring to a phosphate buffer (10 ml, 0,3 aminobenzenesulphonyl)piperidine-3,5-dicarboxylic acid (Example 49, 1.0 g, 3.1 mmol) in N,N-dimethylformamide (5 ml), and maintain the pH at 6.5 to 7.2 by adding 1 N. NaOH. After complete addition, the reaction mixture is heated to 50-55oC and stirred at this temperature for 2 hours (up until HPLC indicates complete reaction), then cooled to room temperature, diluted with water, the precipitated product is filtered, washed with cold water (10 ml), acetone (5 ml) and dried in vacuum at a temperature of 20oC with getting 845 mg (74,2%) of the desired product; so pl. > 250oC, decomp.; MC(ES) m/z 765,0 (M+H); of 764.2 MB.

Example 51

2-Chloro-4,6-bis-[3-(3,5-dicarboxylicacid-1-sulfonyl)- phenylamino]-[1,3,5]-triazine

Specified in the header connection receive in accordance with the method according to example 50, using the acid chloride cyanuric acid (280 mg, 1.5 mmol), 1-(3-aminobenzenesulphonyl)-piperidine - 3,5-dicarboxylic acid (Example 48, 1.0 g, 3.1 mmol), dioxane (3 ml), phosphate buffer (10 ml, 0.3 M, pH 7), N, N-dimethylformamide (5 ml) and 1 N. NaOH. After completion of the reaction the mixture is cooled to room temperature, diluted with water, acidified with HCl to pH 5, the precipitated product is filtered, washed with cold water (10 ml) and dried in vacuum at a temperature of 20oC with getting 845 mg (74,2%) of the desired product; so pl. &is[[3- [[3,5-bis(aminocarbonyl)-1-piperidinyl]sulfonyl]amino]-1,3, 5-triazine-2-yl]amino] benzosulfimide acid

A suspension of disodium salt of 4,4'-diaminostilbene-2,2'-disulfonic acid (0,41 g, 0.1 mmol) and 2-chloro-4,6-bis-[3-(3,5-dicarbonitrile-1-sulfonyl) phenylamino]-[1,3,5]-triazine (Example 50) (1,62 g, 0.21 mmol) in sulfolane (3 ml) and dimethylformamide (5 ml) is heated in the presence of diisopropylethylamine (0,08 ml) in a sealed thin-walled glass tube at a temperature of 115oC. Heating continued for 40 hours. Once the interaction is completed, which is determined using an analytical HPLC (or TLC), the mixture is cooled to 30oC add 1 N. NaOH (0.5 ml) and the product planted by adding propane-2-ol (50 ml). The precipitation is filtered, washed with acetone (30 ml) and re-dissolved in a minimal volume of water and re-planted by adding ethanol. The residue after filtration was washed with ether (30 ml) and dried in vacuum at a temperature of 50oC. the Yield amounts to 1.59 g (85%); MC(ES) m/z 911,7 (M-2H)2-; MB 1869,9 (2Na).

Example 53

Disodium salt of 4', 4-bis-{ 4,6-bis-[3-(3,5 - dicarbonitrile-1-sulfonyl)phenylamino] -[1,3,5] triazine - 2-ylamino}diphenyl-2,2'-disulfonic acid

Specified in the header connection receive in accordance with xplor-4,6-bis-[3-(3,5-dicarbonitrile-1-sulfonyl) -phenylamino]-[1,3,5]triazine (Example 50) (176 mg, 0.23 mmol) in 60 ml of DMSO-sulfolane (1:3, vol/vol) and diisopropylethylamine (0,08 ml). The product is obtained in the form of a solid cream color (153 mg, 83%); so pl. > 250oC, decomp.; MC(ES) (m/z) 898,3 (M-2H)2-; MB 1843,9 (M+2Na).

Example 54

1,2', 1", 1"'-[(2,2'-Disulfo[1,1'-diphenyl] -4,4'-diyl) bis[imino-1,3,5-triazine-6,2,4-Treillis(imino-3,1-phenylenesulfonyl)] tetrakis[3,5-piperidinylcarbonyl acid]

Specified in the header connection receive in accordance with the method according to example 52, using the disodium salt of 4,4'-diaminodiphenyl-2,2'-disulfonic acid (270 mg, of 0.68 mmol) and 2-chloro-4,6-bis-[3-(3,5-dicarboxylicacid-1-sulfonyl) phenylamino]-[1,3,5]triazine (Example 51) (1.1 g, 1,43 mmol) in 60 ml of DMSO-sulfolane (1:1, volume/volume) and diisopropylethylamine (1.2 ml). The product, after planting by adding propane-2-ol, filtered, washed with acetone (30 ml), dried, re-dissolved in a minimal volume of water and re-planted by acidification (HCl) to pH 1-2. The desired product is obtained in the form of a solid cream color (1.0 g, 80%); so pl. > 250oC, decomp.; MC(ES) (m/z) 902,2 (M-2H)2-MB 1807,8.

Example 55

3-Nitrophenyl-N,N-bis(2-hydroxyethyl)sulfonylamino

Diethanolamine (Aldrich; 25,0 g, 0,238 mol) is dissolved in 55 ml of 9:1 methylene chloride/13 mol) in 35 ml THF. The ice bath is removed, the reaction mixture is stirred for another 30 minutes. Then the solvent is drained and the residue partitioned between water (100 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with three portions of ethyl acetate and 25 ml the combined organic layer is dried over MgSO4, filtered through a layer of silicon oxide and concentrated in vacuo. The product is crystallized without further evaporation and filtered with the receipt of 17.4 g (53.2 per cent) of white needle-shaped crystals. So pl. 99-100oC. MC(ES) m/z 291,2 (M+H)1+.

Example 56

3-AMINOPHENYL-N,N-bis(2-hydroxyethyl)sulfonylamino

Nitrosoaniline (Example 55, and 17.2 g of 59.3 mmol) and 1,72 g 10% Pd/C are suspended in 170 ml of ethanol. The mixture restore at a pressure of 40 lb/in2hydrogen for two hours. The catalyst is filtered off and the clear colorless filtrate is evaporated to dryness obtaining of 15.4 g (98% yield) of the corresponding amino compounds. MC(ES) m/z 261,0 (M+H)1+.

Example 57

The disodium salt of 4,4'-bis-(4,6-bis-{3-[bis-(2 - hydroxyethyl)sulfamoyl)phenylamino} -[1,3,5] -triazine-2-ylamino) diphenyl-2,2'-dicarboxylic acid

The solution trichlorotriazine (1.55 g, 8.4 mmol) in 20 ml of dioxane is added to 60 ml of buffer at pH 7 at a temperature ofoC. To the resulting is; ,55 g, 4.0 mmol) in 10 ml of water, maintaining a pH of 6.5 to 7.1 by adding 1 N. NaOH. As soon as the addition of finish and the pH stabilized, the reaction mixture is allowed to warm to ambient temperature. Add a solution of diethanolamide (2.6 g, 10 mmol) in 20 ml of dioxane and solid sodium bicarbonate (0.84 g, 10 mmol) and the resulting mixture heated under reflux (92oC) within two days. Transparent yellow solution is cooled and the layer of dioxane is drained. The product precipitated from the aqueous solution and is collected by vacuum filtration, receiving, and 3.16 g of the desired product, approximately 60% purity by HPLC as a white amorphous solid product. So pl. >250oC, decomp.; MC(ES) (m/z) 732,5 (M+2H)2+; MB 1507,6 (M+2Na).

Example 58

3-AMINOPHENYL-N,N-bis(3-hydroxypropyl)sulfonylamino

A solution of 3-AMINOPHENYL-N, N-bis(2-methoxycarbonylethyl) -sulfonylamino (Example 31, 150 mg, 0.4 mmol) in THF (15 ml) was added to a solution of LiAlH4(3 ml, 1 M in THF) with stirring in nitrogen atmosphere at a temperature of 0oC. After 45 minutes, TLC shows completion of the reaction. To the solution add a solution of ammoniaand (15 ml, 1 M) and a loose white precipitate, and the solution becomes yellow. Yellowish solution de the and a rotary evaporator to give the desired product as a yellow oil. The output is 110 mg (95,6%), (m/z): MH 289,2.

Example 59

The disodium salt of 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(3 - hydroxypropyl)sulfonylamino]-1,3,5-triazine-2-ylamino] diphenyl-2,2'-disulfonic acid

Specified in the header of the get connection using the General conditions of Example 1, where the acid chloride cyanuric acid (92 mg, 0.50 mmol) interacts with the disodium salt of 4,4'-diaminodiphenyl-2,2' -disulfonic acid (93 mg, 0.24 mmol) for 1 hour, and then with 3-AMINOPHENYL-N,N-bis (3-hydroxypropyl) sulfonylamino (708 mg, 2.5 mmol) (Example 58). Once the reaction is finished, which shows analytical HPLC (or TLC), the mixture is cooled to 20oC, and the product is planted by adding propane-2-ol (40 ml), washed on the filter with cold propan-2-I (15 ml) and dried in vacuum at 40 ° oC. Two portions of a solution of the crude product (about 0.35 g) in deionized water (200 ml) is treated separately by preparative HPLC-OFF. The fractions containing the desired product are pooled, the organic solvent is evaporated in vacuum (10 mm RT.CT.) at a temperature of 30oC, and the product concentrate, absoluut and separated on octadecanol (C18) cartridge (900 mg, obtained from Burdick &Jackson). The cartridge was washed with water (yt; so pl. > 300oC, decomp.; MC(ES) (m/z): M-2822,4; MB 1690,8.

THE EFFECT OF THE COMPOUNDS IN THE STUDY OF REDUCTION OF THE OUTPUT OF THE VIRUS.

Compounds are tested for biological activity in experiments on reduction of yield of the virus. Cell owners (referred to as the HRC for foreskin fibroblasts human, and, as a control, a commonly used cell line of African green monkey, in Tables 1 and 1A) place 4 104cells/well in culture medium with 2% fetal bovine serum or 2% calf serum in 96-well plates (0.1 ml/well) and incubated overnight. Compounds added to individual wells, receiving a final concentration consisting in the range from 50 to 0.1 µg/ml at two stages of concentration. After 1 hour, add the virus, and the incubation continued for 4 days with RSV or CMV and within 2 days - with HIV. At the end of the experiment to determine the number of newly formed virus and calculate the reduction of output at various concentrations of compounds. This allows you to evaluate the concentration of compound that gives 50% reduction in growth of the virus (IR50).

In tables 1 and 1A (summary of biological activity) presents the activity of the compounds under study, nienia examined for the ability to inhibit the formation of viral plaques. The cells of the host, as shown in Tables 1, 1a and 2, placed at 10 cells/well in 6-hole tablets and incubated over night. Then follows one of two procedures. Under normal (before treatment) procedure cultural environment replace 1 ml of medium containing the compound at a given concentration. The virus (approximately 100 Blasko-forming units per 40 μl) is added after 1 hour. After 1 hour the medium replaced with 4 ml of medium containing the compound under study at a given concentration. The cells are then incubated for a time sufficient to allow the formation of viral plaques. It is possible to add a connection only after the start of the infection (and subsequent treatment). In this case, the culture medium is replaced by 1 ml of medium containing approximately 100 Blasko-forming units. 1 hour replace 2 ml of medium growth. After another period of time specified in Table 2, add 2 ml containing compound. In any case, the number of plaques in the row of holes containing a set of concentrations of the compound, compared to their number in the hole where there is no connection, and determine IR50graphically, using the received data and determining the concentration of compound that gives 50% of Sakti in the analysis of plaques. As can be seen, the compounds of examples 1 and 4 are active against all the studied strains of RSV, in a concentration of about 0.1 to 0.7 μg/ml Activity can also be observed in relation to certain members of other families of viruses (in the range of 3-20 mg/ml). These results confirm and complement these analyses reduce output, indicating that these compounds are potent and specific inhibitors of RSV.

Table 1. Inhibiting concentration that inhibited growth by 50% (reduced output) and the formation of plaques, defined as described in the text. Used strains of viruses are RSV (A2), CMV (Ad 169), HSV1 (Patton).

Used cell owners are foreskin fibroblasts human (CHR) and the control cells.

Inhibiting concentration that is 50% inhibited growth (reduced output) and the formation of plaques, defined as described in the text. Used strains of viruses are RSV (A2), CMV (Ad 169), HSV1 (Patton). Used cell owners are foreskin fibroblasts human (CHR) and the control cells.

N - no apparent effect on the monolayer of cells, fixed in alcohol and stained what ntalami) monolayer of cells, fixed in alcohol and stained with the dye crystal violet, for a given concentration of the compound, but not at half the concentration.

In the Protocol pre-treatment confluent cells in 6 - hole cups treated with various concentrations of compounds for 1 hour. The virus (approximately 100 PFU) is added in small volume, and believe plaques after incubation (RSV, CMV and PUGS (parovirus human influenza, type 3, strain Washington), 5-8 days; influenza virus and herpes simplex 2 days). When processing after infection, cells initially infect over 1 hour, and the environment (containing needsomeone viruses) are removed. The medium containing the compound at various concentrations, add 2 hours or 24 hours after the end of the period of infection. Used cells include control (cells of the African green monkey), CHR (cells foreskin fibroblasts human), CNBC (cells human neuroblastoma), KBMT (kidney cells bull Madin-Darby) and CPCMD (cells of the kidney of the dog Madin-Darby).

THE MECHANISM OF ACTION

For a better understanding of the mechanism of action define the life cycle of viruses, when the compound of example 1 has an effect. This is achieved by dobavleniya on the synthesis of viral proteins. Control infect cells on ice for 1 hour, neadsorbirovanne the virus is removed, and then the infected cells are incubated at a temperature of 37oC for 18 hours (on ice is the adsorption of the virus, but the merger will not occur as long as the temperature does not rise to the 18oC or higher). After 18 hours incubation at a temperature of 37oC (when the amount of ongoing protein synthesis is controlled by the RNA virus), within 2 hours add35C methionine, the cells lyse and labeled proteins analyzed on gels SDS-PAGE. Then detect viral proteins N, P and M. If the compound of example 1 is added in an amount of 10 μg/ml directly after adsorption of the virus and before raising the incubation temperature to 37oC, the fusion proteins of the virus completely prevented. However, when the compound of example 1 add at least after 5 minutes incubation at 37oC, effect on the synthesis of viral proteins does not occur. Therefore, inhibiting the process is the merger or any directly next stage, which is necessary for the subsequent expression of viral gene.

It is known that RSV-infected cells in close contact will be with whom.G., Gustafson, E., Bernstein J. M. , Galinski, M. S. 1994. Analysis of respiratory syncytial virus F, G and SH proteins in cell fusion. Virology 200; 801-805). The formation of syncytium should not affect the function of the virus, such as the removal of the shell or transcription, which usually follows it and which are necessary for the subsequent expression of viral gene.

To determine inhibit whether the compounds of the present invention, the merger or the subsequent stage, they are tested on the ability to prevent the formation of a syncytium of cells previously infected with RSV. This is carried out by infection control cells by triple infection for 1 hour, then replacing the original medium with fresh medium. After 6 hours incubation, add the connection. After 24 and 48 hours, infected cells are examined under a microscope to determine the extent of syncytium formation. Differences in the extent of syncytium formation, caused by the presence of compounds that are easily noticeable, and connections easily classified in terms of their saledate this analysis. Real values IR50as set using this method are close to each other. They are 0.3 and 0.05 mg/ml for compounds 16 and 17, respectively. Poisning cycle of the virus.

THE COMPOUNDS OF EXAMPLES 1 AND 4 PREVENT THE GROWTH OF RSV IN VIVO. To assess the anti-RSV potential of compounds in vivo using a RSV infection in cotton rats after intake of medication in aerosol form of small particles (AMD). (Gilbert C. E., Wyde, P. R., Wilson, S. Z., and Meyerson L. R. 1993. SP-303 small particle aerosol treatment of influenza A virus infection in mice and respiratory virus infection in cotton rats. Antiviral Research 21; 37-45).

Compounds of the present invention are examined in order to determine whether they can inhibit the growth of RSV in cotton rats. In experiment 1 (see Table 3) animals infect intranasal RSV A2 (day 0), which leads to respiratory infections. Ribavirin is used in the form of a 60 mg/ml in water in the spray and injected over 2 hours twice daily on days 1, 2 and 3 after infection. The connection 16 is used in the form of 4 and 5 mg/ml in 25 mm NaHCO3in the nebulizer and administered for 4 hours before infection and for 8 hours on each of days 1, 2 and 3. Placebo is the water used in the same mode as the connection 16.

Slaughtered at day 4, light wash and determine the titers of RSV in the drilling fluid. In experiment 2 infected untreated animals and animals exposed to aerosol of 25 mm NaHCO3serve kcevayt compound of example 1 for 4 hours prior to infection on day 0 and for 8 hours on each of days 1, 2 and 3 (preventive mode). One group treated with compound of example 1 for 8 hours only each day 1, 2 and 3 (therapeutic treatment). The last group treated with the compound from example 4 for 8 hours in each of days 1, 2 and 3 (therapeutic treatment). In day 4, all animals were slaughtered, light wash and determine the titers of RSV in the drilling fluid. In experiment 3 placebo water is injected intranasally once a day. Connection example 4 explore via the intranasal route by dosing before vaccination and on the next day thereafter (days 0 and 1), by dosing before vaccination and on days 1 - 3, and by dosing only once vaccinated on days 1-3. The compound is also examined by introducing intraperitonal. On day 4, all animals were slaughtered, their lungs are washed and determine the titers of RSV in the drilling fluid. Do this by determining the end-point dilution, which has cytopathologically action (JRC) in control cells, as well as by analysis of plaques in the control cells. Light also homogenized and determine the titres of light by centrifugation and precipitation of material particles (1000 g, 10 minutes) and using dilution of supernatants in the analysis of plaques. the organisations of General formula I

< / BR>
where a represents a radical selected from the group including

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
With' is selected from-SO3H or COOH;

In' selected from NR1or, where R1selected from H or (C1-C6) alkyl straight or branched chain;

X is selected from Cl or radical

< / BR>
where U' is selected from the group comprising-SO2- or-CO-, -NHC(O)- or-NHC(S);

W is selected from the radicals:

< / BR>
where Y represents -(CH2)n-;

n is 0-6;

m is 0-2;

Z is selected from H, CH2OH, COOH or CONR2R2where R2in each case independently selected from H or (C1-C6)alkyl,

or their pharmaceutically acceptable salt or ester.

2. Connection on p. 1, where a represents the radical

< / BR>
where C' is-SO3H;

W' is a radical:

< / BR>
where Y is-CH2-;

Z = -CH2OH;

U', X, Y, n and m are as stated in paragraph 1,

or its pharmaceutically acceptable salt or ester.

3. Connection on p. 1, where a is a radical

< / BR>
where C' is-SO3N;

W' is a radical:

< / BR>
where Y is-CH2CH2-;

Z = -CONH2;

U', X, Y, n and m are the same under item 1, in which the pharmaceutically acceptable salt is the disodium salt.

5. Connection on p. 1, which is 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] - 1,3,5-triazine-2-ylamino] stilbene-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

6. Connection on p. 1, which is 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] diphenyl-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

7. Connection on p. 1, which is 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2-hydroxyethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] stilbene-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

8. Connection on p. 1, which is 4-[4,6-di[3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino]-4'-[4-chloro-6-[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino]-stilbene-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

9. Connection on p. 1, which is 4,4'-bis[4-chloro-6-[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino]stilbene-2,2'-disulfonic acid or its pharmaceutically acceptable Sol] -1,3,5-triazine-2-ylamino] -4'-[4-[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -6-[3-AMINOPHENYL-N-(2-carbamoylethyl)-N'-(3-propionic acid)] -1,3,5-triazine-2-ylamino]stilbene-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

11. Connection on p. 1, which is 4-[4,6-di[3-AMINOPHENYL-N,N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] -4'-[4-[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino]-6-[3-AMINOPHENYL-N,N-bis(3-propionic acid)] -1,3,5-triazine-2-ylamino] stilbene-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

12. Connection on p. 1, which is 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] dibenzyl-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

13. Connection on p. 1, which is 4,4'-bis[4,6-di[4-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] stilbene-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

14. Connection on p. 1, which is 4,4'-bis[4,6-di[4-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] diphenyl-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

15. Connection on p. 1, which alleycatallies acceptable salt.

16. Connection on p. 1, which is 4,4'-bis[4,6-di[3-aminophenylacetamido] -1,3,5-triazine-2-ylamino]diphenyl-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

17. Connection on p. 1, which is 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-yloxy]diphenyl-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

18. Connection on p. 1 which is 5,5'-dimethyl - 4,4'-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)-sulfonylamino] -1,3,5-triazine-2-ylamino]diphenyl-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

19. Connection on p. 1, which is 4,4'-bis [4,6-di[3-AMINOPHENYL-N, N-bis(2-hydroxyethyl)sulfonylamino] -1,3,5-triazine-2-ylamino]diphenyl-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

20. Connection on p. 1, which is 9,9-dioxo-2,7-bis[4,6-di[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)sulfonylamino] -1,3,5-triazine-2-ylamino] dibenzothiophen-3,6-disulfonic acid or its pharmaceutically acceptable salt.

21. Connection on p. 1, which is 4,4'-bis[4-chloro-6-di[4-amino-N'-[3-AMINOPHENYL-N, N-bis(2-carbamoylethyl)-sulfonylamino] benzamide]-1,3,5-triazine-2-ylamino] Otoro is 4,4'-bis[4,6-di[4-amino-N'-[3-AMINOPHENYL-N, N-bis(2-hydroxyethyl)-sulfonylamino] benzosulfimide] -1,3,5-triazine-2-ylamino] stilbene-2,2'-disulfonic acid or its pharmaceutically acceptable salt.

23. Connection on p. 1, which is the disodium salt of 4,4'-bis[4,6-bis{ 3-[bis-(2-carbamoylethyl)sulfamoyl]-phenylamino}-1,3,5-triazine-2-ylamino]-diphenyl-2,2'-dicarboxylic acid.

24. Connection on p. 1, which is the disodium salt of 4,4'-bis-[[4,6-bis[[3-[[bis-[3-(methylamino)-3-oxopropyl] amino] sulfonyl] phenyl] amino]-1,3,5-triazine-2-yl]amino][1,1'-diphenyl]-2,2'-disulfonic acid.

25. Connection on p. 1, which is the disodium salt of 4,4'-bis(4,6-bis(3-[bis-(2-methylcarbamoylmethyl)-sulfamoyl] phenylamino} -[1,3,5]-triazine-2-ylamino]diphenyl-2,2'-dicarboxylic acid.

26. Connection on p. 1, which is the dimethyl ether of 4,4'-bis-(4,6-bis{ 3-[bis-(2-carbamoylethyl)-sulfamoyl] phenylamino}-[1,3,5]-triazine-2-ylamino] diphenyl-2,2'-dicarboxylic acid or its pharmaceutically acceptable salt.

27. Connection on p. 1, which is the disodium salt of 4,4'-bis-(4,6-bis-{ 3-[bis-(2-hydroxypropyl)- sulfamoyl] phenylamino} -[1,3,5] -treein-2-ylamino]diphenyl-2,2'-disulfonic acid.

28. Connection on p. 1, which is Dina the dicarboxylic acid.

29. Connection on p. 1, which is the disodium salt of 4',4-bis-{ 4,6-bis-[3-(bis-carbamoylmethyl-1-sulfamoyl)phenylamino] -[1,3,5]-triazine-2-ylamino}diphenyl-2,2'-disulfonic acid.

30. Connection on p. 1, which is the disodium salt of 4',4-bis-{ 4,6-bis-[3-(bis-carbamoylmethyl-1-sulfamoyl)phenylamino] -[1,3,5]-triazine-2-ylamino}diphenyl-2,2'-dicarboxylic acid.

31. Connection on p. 1, which is the disodium salt of (E)-2,2'-(1,2-ethandiyl)bis[5-[[4,6-bis[[3-[[3,5-bis(aminocarbonyl)-1-piperidinyl] sulfonyl]phenyl]amino]-1,3,5-triazine-2-yl]benzosulfimide acid].

32. Connection on p. 1, which is the disodium salt of 4',4-bis-{ 4,6-bis-[3-(3,5-dicarbonitrile-1-sulfonyl)phenylamino] -[1,3,5] triazine-2-ylamino}diphenyl-2,2'-disulfonic acid.

33. Connection on p. 1, which is 1,2',1",1"'-[(2,2'-disulfo[1,1'-diphenyl] -4,4'-diyl) bis[imino-1,3,5-triazine-6,2,4-Treillis(imino-3,1 - phenylenesulfonyl)] tetrakis[3,5-piperidinecarboxylic acid or its pharmaceutically acceptable salt.

34. Connection on p. 1, which is the disodium salt of 4,4'-bis-(4,6-bis-{ 3-[bis-(2-hydroxyethyl)sulfamoyl] -phenylamino}-[1,3,5]-triazine-2-ylamino}diphenyl-2,2'-dicarboxylic acid.

35. The connection is iasen-2-ylamino]diphenyl-2,2'-disulfonic acid.

36. Connection on p. 1, its pharmaceutically acceptable salt or ester possessing antiviral activity in mammals.

37. Connection on p. 36, possessing antiviral activity at a dose of about 10 to 500 mg/kg

38. Connection on p. 36, where the viral infection is respiratory syncytial virus infection.

39. Connection on p. 36, where the viral infection is an infection of the herpes simplex virus.

40. Connection on p. 36, where the viral infection is an infection of the human immunodeficiency virus.

41. Connection on p. 36, where the viral infection is cytomegalovirus infection.

42. Pharmaceutical composition having antiviral activity, containing an effective amount createnodeviewer anionic compounds of General formula I:

< / BR>
where a represents a radical selected from the group including

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where C' is selected from-SO3H or COOH;

In' selected from NR1or, where R1selected from H or (C1-C6) alkyl straight or branched chain;

X is selected from CL or radical

< / BR>
where U' is selected from the group comprising-SO2- or-CO-, -N(O)- or-NHBR> Z is selected from H, CH2HE, COOH or CONR2R2where R2in each case independently selected from H or (C1-C6)alkyl,

or its pharmaceutically acceptable salt or ester and one or more pharmaceutically acceptable carriers or excipients.

Priority points

13.02.1996 - all claims;

27.01.1997 - examples 28-59.

 

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