Substance with antiviral and antibacterial activity based on derivatives of 2,8-dithioxo-1h-pyrano[2,3-d; 6,5-d']dipyrimidine and their 10-aza-analogues

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

 

The invention relates to the field of organic chemistry and medicine, specifically to a synthetic derivative of pyrimidine -2,8-dicicco-1H-pyrano[2,3-(1; 6,5-d']dipyrimidine and their 10-Aza-analogs and their complexes and salts, which has antiviral and antibacterial activity. The invention is intended mainly for use in medicine and veterinary medicine for the treatment of viral diseases and diseases caused by bacteria, and in cosmetics as an additive for the prevention and treatment of infections.

As you know, many pyrimidine derivatives possess significant biological activity and participate in the life processes of organisms [1 - Dawson R. and other Reference biochemist. M., Mir, 1991, 544]. Of great importance are synthetic derivatives of pyrimidine, of which extensive use in medicine has gained substituted barbituric acids, orally and others [2 - Mashkovsky PPM Drugs, 14th ed., M., "New Wave", 2000]. Data on the biological activity of 5-riceproducing barbituric acids are summarized in the review [3 - Sans R.G., Chosas M.G. // Pharmazie, 1988, 43 Bd, N12, S.827-829]where noted anticonvulsant, antimicrobial, antispasmodic, antipyretic, antitumor activity of these substances. The obtained data on the biological activity of some 5-aileenbarclay acids Singh A. and others // Phrmacol. Res., 1989, Vol.21, No.1, P.59-64 (Chemical Abstracts, Vol.11, 49906z); Japan Patent No 05213755, publ. 24.08.1993 (Chemical Abstracts, 1993, Vol.119, 262520 g); A. Kumar, etc. // Indian J. Chem. Sect. 1988, Vol.27, N5, P.443-447], 5-aminomethyltransferase acid [9-.Kreutzberger A. and others // Arch. Pharm., 1983, Bd 316, N. 1, S.6-9], 5-arylcarbamoyl acids [10, 11 - Minatelli J.A. and other Germany application No. 3446371, publ. 27.06.1985; Brewer A.D. U.S. Patent No. 4920126, publ. 24.04.1990]. High activity was observed also in annelated derivatives of pyrimidine, such as pyrazolo[3,4-d]pyrimidine, [12-Naka T. and other EPO application no. 237289 (1987)], 5-diazepino [13, 14-.Kimachi Etc. etc. // J. Heterocycl. Chem., 1992, Vol.29, No.4, P.763-765; 5-dialkylaminomethyl [19-M.S. Motawia, etc. // Monatsh. Chem., 1993, Bd 124, N. 1, S.55-64], pyrimido[4,5-C]pyridazines [20 - Billings B.K., etc. // J. Heterocycl. Chem., 1975, Vol.12, N6, P.1221-1224]. These compounds possess pesticidal, antitumor, antimicrobial, immunosuppressive, nootropic, antihypertension and antiallergic action.

At the same time, many groups pyrimidine derivatives remain virtually unexplored, on the one hand, due to their synthetic inaccessibility, and on the other hand, due to the lack of objective criteria to advance to expect that they will exhibit the desired biological activity, and will not yet have high toxicity and other side effects. Therefore, despite theoretical and practical difficulties, inches new groups pyrimidine derivatives and study of their biological activity, remains an important direction of search for effective treatments for major diseases of mankind. In this regard, particular interest is the synthesis of compounds of rare and little-investigated group - derived pyrano[2,3-d: 6,5-d']dipyrimidine. To date, only known to a few isolated examples of education pyranopyrandiones system, in particular, in the interaction of barbituric acid with 3-allegramente [21, 22 - F. Eiden, etc. // Chemische Berichte, 1968, Bd 101, N8, S.2894-2898; [21, 22 - F. Eiden, etc. // Chemische Berichte, 1968, Bd 101, No. 8, S.2894-2898; F. Eiden et al.// Arch. Pharm., 1972, Bd 305, N 3, p. 187-193]. Information about their biological activity are absent.

The closest to the claimed compounds on chemical structure and purpose are derivatives of 5H-pyrano[2,3-d:6,5-d']dipyrimidine having antibacterial, antiviral and immunomodulatory effects [23 Ashkenazi RI. PCT/RU97/00371 from 19.11.1997, patent RU 2188201]. This connection is chosen as a prototype. When this substance prototype have limited spectrum antiviral and antibacterial actions: they are not active against influenza viruses are not or little active against retroviruses.

The task of the invention to provide new, more effective chemical compounds with antiviral and antibacterial action.

The problem is solved by the synthesis of new substances of General formula is A1*M:

where X is selected from the group: O, NH, N-Alkyl;

R1 is selected from the group: H, HE, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar, N(Alkyl)2, SH, S-Alkyl;

R2 is selected from the group: phenylmethylene or substituted, naphthyl, thienyl;

R3 is selected from the group: H, Cl, O-Alkyl, NH2, NH-Alkyl, S-dihydroxypyrimidine;

M is absent or selected from the group of cations Na, K, Li, ammonium, or any other pharmacologically acceptable cation; or a complex pharmacologically acceptable cation (see above) with the anion of one of the derivatives of A1 (options R1-R3 defined above).

In this series of experiments, the best activity among the stated substances A1*M (where M is absent) showed the following derivatives:

As can be seen from the above materials, declare us derivatives pyrano[2,3-d: 6,5-d']dipyrimidine A1*M differ from the prototype by the presence of other functional groups in the pyrimidine fragments and cannot be obtained by the methods specified in the prototype. It should be noted that the presence of high biological activity of the inventive substances does not follow from the current level of technology, as pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues are complex and currently under-researched group for new members which spectrum and level of activity is not a foreseeable, the AMB in advance. The inventive substances are new, since they are absent in the well-known sources of information. Thus, the invention is novel, non-obvious and has the following advantages over currently known samples.

It should be noted that the invention applies not only to the most active compounds (Ia, Ib, IIA, III-XII) and their complex salt (XIII-XV), but also on all derivatives A1*M provided by the invention. Our studies showed that all substances derived from the proposed General method of synthesis, have declared activities in varying degrees. This allows to conclude that for process synthesis and biological properties of the claimed compounds, the most essential are not private structural features of the radicals R1, R2, R3, and their belonging to a specified General formula chemical groups.

The invention is illustrated below information:

A) Synthesis and analysis of the claimed compounds:

General method of synthesis of two stages.

Examples of the synthesis of the claimed substances, where:

Example 1 - an embodiment of the first stage of synthesis of the intermediate (and simultaneously the target of the product, namely 4-chloro-6-hydroxy-5-aryl-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (Ia).

Example 2 - you is filling up the first stage of synthesis of the intermediate (and simultaneously the target of the product, namely-4,6-dichloro-5-aryl-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (IIA).

Example 3 - an embodiment of the second stage of synthesis of the target product, namely 4-amino-6-hydroxy-5-aryl-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (III).

Example 4 - an embodiment of the second stage of synthesis of the target product, namely 4-chloro-6-amino-5-(4-nitrophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (IV).

Example 5 - Option for the second stage of synthesis of the target product, namely -4,6-diamino-5-aryl-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (V).

Example 6 - embodiment of the second stage of the synthesis of the target product, namely -4,5-diamino-10-aryl-9,10-dihydro-1H, 8H-1, 3, 6, 8, 9-pentosanase-2,7-dition (VI).

Example 7. - Option for the second stage of synthesis of the target product, namely 4-(4,6-dihydroxypyrimidine-2-sulfanyl)-6-hydroxy-5-aryl-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (X).

Example 8 is a Variant of the second phase of the synthesis of the target product, namely-6-hydroxy-5-(4-nitrophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (XI).

Example 9 is a Variant of the second phase of the synthesis of the target product, namely a complex of salt XIII, which includes the compounds Ib, XII and ammonia {1b (1 mol), XII (1 mol), NH3(1 mol)}.

Example 10 - embodiment of the second e is APA - the synthesis of the desired product, namely a complex of salt XIV, which consists of compound III, XII and ammonia {III (1 mol), XII (1 mol), NH3(1 mol)}.

Physico-chemical characteristics, have two pivot tables:

Table 1 - PMR spectra of the claimed compounds

Table 2 - temperature decomposition and elemental analysis results.

B) Experimental determination of the biological properties of the claimed compounds:

Example 11 - determination of the effect on the herpes virus (Table 3).

Example 12 determination of the action on Chlamydia trachomatis (Table 4).

Example 13 - definition of action on influenza viruses a and B (Table 5)

Example 14 determination of activity against human immunodeficiency virus (Table 6).

Example 15 Use of the claimed compounds together with the drugs used for treatment of AIDS (Table 7).

Example 16 - determination of the acute toxicity of the inventive substances.

A. ANALYSIS AND SYNTHESIS of the CLAIMED COMPOUNDS

General method for the synthesis of the claimed compounds (two stages).

Our proposed synthesis involves two main stages:

First stage: Synthesize 5-arylphosphonate 4-chloro-6-hydroxy-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (Ia, b) or 4,6-dichloro-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (IIA) from the corresponding aromatic aldehydes and 2-thio is orbicurves acid followed by treatment l 3or other gloriously and dehydrating agents. Resulting intermediate compound (Ia, b IIA, and their analogs) are also targeted, as they have a sufficiently high level of the claimed biological activity.

Second etapestry target compound (III-V, VIII-XII and their analogues, where X=O, R1=OH, unsubstituted or substituted amino group, R2=unsubstituted or substituted benzene ring, R3 is unsubstituted or substituted amino group, or alkoxygroup, unsubstituted or substituted mercaptopropyl) obtained at the first stage of intermediate compounds (I and II) by substitution of one or two chlorine atoms in tricyclic 1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-ditionally system NH2, alkylamino or dialkylamino, alkoxygroup, SH, alkylthio, aaltio or getaltitude by processing the corresponding nucleophilic reagents (amines, alcoholate or thiolate);

- Synthesize the target compounds (VI, VII, and their analogues, where X=NH or N-Alkyl, R1=OH, unsubstituted or substituted amino group, R2 is unsubstituted or substituted benzene ring, R3 is unsubstituted or substituted amino group) obtained at the first stage of intermediate compounds (Ia, b and IIA) by substitution of one or two chlorine atoms in tricyclic 1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-ditionally system NH2or alkylamino, with the simultaneous exchange of Pyrenophora atom of oxygen (O10) on the amino group;

- Synthesize the target compounds (XI and its analogues, where R2 is unsubstituted or substituted benzene ring) obtained at the first stage intermediate substance (Ia) by means of its restoration dehalogenase;

- Synthesize the target compounds (complex salt XIII-XV) by dissolving equimolar quantities of compounds III and XII or XI and XII, or Ib and XII in excess of ammonia, and with the further acidification of the solution.

Example 1. A variant of implementation of the first phase synthesis of intermediate (and simultaneously the target of the product, namely 4-chloro-6-hydroxy-5-phenyl-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (Ia).

Dissolve 0.1 mol 2-thiobarbituric acid (XVI) in 50 ml of dimethylacetamide. To this solution under stirring was added a mixture of 0.05 mol of benzaldehyde * and 0.05 mol of base (triethylamine) in a solution of dimethylacetamide. After a few hours, diluted with ether, the precipitate washed with ether and dried triethylammonium salt XVII.

To the resulting salt XVII (27 g) is poured 0.3 mol l3, 100 ml of chloroform and boil for 3 hours Then the solvent is distilled off, to the residue was added water and the separated solid is washed with water and dried. Get the product of Ia with the release of 81%.

*Note. 4-Chloro-6-hydroxy-5-(4-nitro the Nile)-5,9-dihydro-1H-pyrano[2,3-d; 6,5-d']dipyrimidine-2,8-dition (Ib) and 4-chloro-6-hydroxy-5-(4-chlorophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (IC) are obtained according to a similar method (exit 84 and 77%) when using p-nitrobenzaldehyde or p-chlorobenzaldehyde instead of benzaldehyde, respectively.

Likewise, when the use of other aromatic aldehydes are obtained the corresponding 5-arylphosphonate 4-chloro-6-hydroxy-5,9-dihydro-1H-pyrano [2,3-d : 6,5-d']dipyrimidine-2,8-dition (see General formula, X=O, R1=OH, R2=Aryl, R3=Cl, M - no). According to the derivative Id-Li (transcript radicals - see General formula):

n-methylbenzaldehyde - Id (R1=OH, R2=n-tolyl, R3=C1);

from n-forventelige - Ie (R1=OH, R2=C6H4-F(p), R3=C1);

from n-ethoxybenzaldehyde - If(R1=OH, R2=C6H4-OEt(p), R3=C1);

from 3,4-dimethoxybenzaldehyde - Ig (R1=OH, R2=C6H3-3,4-(OMe)2, R3=C1);

1-naphthaldehyde - Ih (R1=OH, R2=1-Naphthyl, R3=C1);

from thiophene-2-aldehyde - Ii (R1=OH, R2=2-Thienyl, R3=C1).

We do not list all of these options, limited to the most active representatives (Ia, Ib), are shown in table 1.

Example 2. A variant of implementation of the first phase synthesis of intermediate (and simultaneously the target of the product, namely 4,6-dichloro-5-(4-nitrophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (IIA).

To 0.1 mol of 2-thiobarbituric acid (XII) in 50 ml of p is Regina added 0.05 mol of p-nitrobenzaldehyde and heat the mixture until complete dissolution. After a few hours, diluted with ether, the precipitate washed with ether and dried pyridinium salt (XVIII).

To the resulting salt XVIII (26,5 g) is poured 0.5 mol POCl3* and heated under reflux for about 1 h to dissolve the precipitate. Then the excess POCl3distilled off, to the residue was added water and the separated solid is washed with water and dried. This substance is newly added 0.5 mol l3and repeat the above procedure. After washing and drying receive the product IIA exit 77%.

*Note. A similar technique, using instead l3triperoxonane anhydride, get 4,6-dihydroxy-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition XII and its analogues (see General formula, X=O, R1=R3=OH, R2=Aryl, M is missing)

Example 3. A variant of the second phase of the synthesis of the target product, namely 4-amino-6-hydroxy-5-(4-nitrophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (III).

0.01 mol of compound IB with stirring portions are dissolved in 30 ml of 25%aqueous ammonia *. Undissolved substance is separated and the solution incubated day at room temperature, then diluted with water and acidified to pH 5-6. The residue is separated, washed with water, alcohol, and dried. Get the product III with 71%yield.

*Note. A similar technique, when COI is the whether of methylamine instead of ammonia, get a 4-methylamino-6-hydroxy-5-(4-nitrophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (VIII), yield 78%) and 4-dimethylamino-6-hydroxy-5-(4-nitrophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (IX), the yield was 73%. The methodology described in example 3, is General and allows similarly, on the basis of other 5-arylpropionic 4-chloro-6-hydroxy-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition, by substitution of the chlorine atom in the reaction with ammonia or alkylamines followed) at the amino group, to obtain the corresponding 5-aryl-4-amino derivatives of 6-hydroxy-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (see General formula, where X=O, R1=OH, R2=unsubstituted or substituted phenyl or other aryl, R3=NH2or NHAlk or NAlk2M is absent). We do not list all of these options, limited to the most active representatives of (III, VIII, IX), are shown in table 1.

Example 4. A variant of the second phase of the synthesis of the target product, namely 4-chloro-6-amino-5-(4-nitrophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (IV).

To 0.01 mol of compound IIa poured 10 ml of ethanol containing 0.02 mol NH4OH, and mix. The mixture is kept for a day at room temperature, then diluted with water and acidified to pH 5-6. The residue is separated, washed with water and dried. Get the product of IV with the release of 54%.

0.01 mol of compound IIa with stirring portions are dissolved in 30 ml of 25%aqueous ammonia. Undissolved substance is separated and the solution incubated day at room temperature, then diluted with water and acidified to pH 5-6. The residue is separated, washed with water, alcohol, and dried. Get the product of V with the release of 66%.

*Note. The methodology described in example 5, is General and allows similarly, on the basis of other 5-arylpropionic 4,6-dichloro-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition, to replace the chlorine atoms in the reaction with ammonia or alkylamines followed) at the amino group to obtain the corresponding 5-aryl-4,6-diamine-derivates 5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (see General formula, where X=About, R1, R3=NH2or NHAlk or NAlk2, R2=unsubstituted or substituted phenyl or other aryl, M is absent). We do not list all of these options, limited to the most active representatives of (III, VIII, IX), are shown in table 1.

Example 6. A variant of the second phase of the synthesis and preparation of the target product, such as 4,5-diamino-10-(4-nitrophenyl)-9,10-dihydro-1H, 8H-1, 3, 6, 8, 9-pentosanase-2,7-dition(VI).

0.01 mol of compound IIA dissolved in 80 ml of 25%aqueous ammonia. The solution is filtered from undissolved particles and heat up the night with reflux. Then evaporated to 40 ml, cooled, precipitated precipitate is washed with water, alcohol, and dried. Get the product of VI with the release of 31%.

Note. Similar to the method of compound IC (see Example 1) receive a 4-hydroxy-5-amino-10-(4-chlorophenyl)-9,10-dihydro-1H, 8H-1, 3, 6, 8, 9 -pentosanase-2,7-dition(VII).

Example 7. A variant of the second phase of the synthesis of the target product, namely 4-(4,6-dihydroxypyrimidine-2-sulfanyl)-6-hydroxy-5-(4-nitrophenyl)-5,9-dihydro 1H-pyrano[2,3-d : 6,5-d']dipyrimidine 2,8-dition (X).

0.015 mol of 2-thiobarbituric acid (XVI) under stirring dissolved in 20 ml of water containing 0.03 mol NaOH. To the resulting solution was poured 20 ml of dimethyl sulfoxide, then add a solution of 0.01 mol of compound Ib in dimethyl sulfoxide and stirred for several hours at room temperature. The solution was diluted with water, acidified to pH 5-6 deposited precipitate was separated, washed with water, alcohol, and dried. Get the product of X with the release of 42%.

Example 8. A variant of the second phase of the synthesis of the target product, namely-6-hydroxy-5-(4-nitrophenyl)-5,9-dihydro-1H-pyrano[2,3-d : 6,5-d']dipyrimidine-2,8-dition (XI).

0.01 mol the compound Ib dissolved in 25 ml of glacial acetic acid. To this solution over a period of 0.5 h with stirring was added in small portions 0.02 mol NaBH4maintaining the temperature not higher than 30°C. Stirred for further 4 h and poured the mixture into water, the precipitated precipitate was separated, washed with water, alcohol and recrystallized from dimethylformamide. Get the product of XI with the release of 36%.

Example 9 is a Variant of the second phase of the synthesis of the target product, namely a complex of salt XIII, which includes the following ingredients: compound Ib (1 mol), compound XII (1 mol) and NH3(1 mol).

0.01 mol of compound Ib * and 0.01 mol of compound XII is dissolved under stirring without heating in 200 ml of 0.5% ammonia. Nerastvorim the residue was separated and treated with a new portion 50 ml of 0.5% ammonia. United clear solution is acidified with acetic acid and incubated for several hours at room temperature. The precipitation was separated, washed with water, alcohol, and dried. Obtain 6.9 g of compound of salt XIII, yield 80%.

*Note 1. A similar technique when using Ib instead of other compounds (III or XI) are respectively the complex salt of the XIV and XV.

Example 10 - embodiment of the second stage of the synthesis and preparation of the desired product, namely a complex of salt XIV, which includes the following substances: III (1 mol), XII (1 mol) and NH3(1 mol).

To 0.01 mol pyridinium salts XVIII (see Example 2) poured 12 ml l3and heated under reflux for about 40-50 minutes until such time as the majority of sediment does not go into solution. Decanted the solution from the precipitate and evaporated to 5 ml l3, poured into ice and, after hydrolysis, separating the solid and washed with water. To the obtained product was added 40 ml of water and 10 ml conc. ammonia and stirred for 4 hours without heating, with the majority of sediment is dissolved. The solution is filtered from undissolved particles and acidified with acetic acid. After a few hours the precipitation is filtered, washed with water and dried. Get the product XIV with 71%yield.

PHYSICO-CHEMICAL CHARACTERISTICS of the CLAIMED SUBSTANCES

11.11 (1H), 12.20 (1H), 13.35 (1H)
Table 1.

The PMR spectra of the claimed substances (DMSO-d6that δ, ppm, J, Hz)
No.C(5)H 1H,s*ArNH (HE) USSNH2(NMe) USS
la5.026.79 (1H, t), 7.16 (2H, t), 7.33 (2H, d) J 8.011.05 (1 N), 12.44 (1 N), 13.55 (1 N)-
Ib5.037.54 (2H, d) 8.02 (2H, d), J 8.411.18(1H),12.35(1H),13.40(1H)-
Ic5.017.14 (2H,d) 7.45 (2H, d), J 8.4-
IIa5.397.56 (2H, d), 8.04 (2H, d), J 8.312.91 (2N)-
III4.947.50 (2H, d), 7.92 (2H, d), J 8.311.80(2N),12.84(1H)11.96 (21-1)
IV5.107.52 (2H, d) 8.00 (2H, d), J 8.012.70(2N)12.25 (2N)
V4.997.48 (2H, d), 7.89 (2H, d), J 8.212.84(2N)11.90 (41-1)
VI4.547.52 (2H, d) 8.00 (2H, d), J 8.412.90(3H)11.66 (41-1)
VII4.667.16 (2H,d), 7.33 (2H, d),J 8,011.15(1H), 12.91 (2N)12.34 (2N)
VIII4.857.52 (2H, d), 8.04 (2H, d), J 8.411.20(1H), 12.45(3H)3.59 (3H, s)
IX4.95+5.197.65 (2H, d), 7.86 (4H, m), 8.07 (2H, d), J 8.011.10(2N), 12.85 (3H)-
XS5.28 (1H, s), 7.56 (2H, d), 8.04 (2H, D), J 8.111.23(1H), 12.35 (4N)-
XI5.027.55 (2H, d), 7.97 (2H, d), 8.31 (1H, s)11.14(1H), 12.80 (2N)-
XII4.757.65(2H, d), 8.11 (2H, d),e12.55 (2N), 13.9 (2H, ush) -
XIII4.80 ush7.55 (4H, ush) 8.10 (4H, ush)9.11 (1H ush), 11.05 (2H, ush); 12.457.25 (4H ush)
 5.25 ush (2H, ush) 
XIV4.95 ush7.53 (4H, ush) 8.12 (4H, ush)10.00-13.50 (5H, ush)7.24 (4H ush)
 5.13 ush   
XV4.95 ush7.50 (4H, ush) 8.07 (4H, ush); 8.35 (1H, ush)9.70-13.40 (5H, ush)7.25 (4H ush)
 5.13 ush   
*s - singlet, ush. C. broadened singlet, d - doublet, t - triplet, m = multiplet

16.32
Table 2.

Temperature of decomposition and elemental analysis data of the claimed substances
Ia23047.902.479.3314.5517.19C15H9ClN4O2S247.812.419.4114.8717.02
Ib230At 42.561.988.2315.14C15H8ClN5O4S242.711.918.4016.6015.20
Ic24543.651.9917.0813.4615.43C15H8ClN4O2S243.811.9617.2413.6215.59
Id24043.651.9917.0813.4615.43C16H11ClN4O2S249.172.849.0714.3316.41
Ie24545.631.9917.0813.4615.43C16H8ClFN4O2S245.632.048.9814.1916.24
If23543.651.9917.0813.4615.43C17H13ClN4O3S248.513.118.4213.3115.24
Ig23543.651.9917.081.46 15.43C17H13ClN4O4S246.743.008.11At 12.82At 14.68
Ih23043.651.9917.0813.4615.43C19H11ClN4O2S253.462.608.3013.1215.02
Ii23043.651.9917.0813.4615.43Cl3H7ClN4O2S3At 40.781.849.268.3625.12
IIa24040.711.5515.9215.8814.34C15H7Cl2N5O3S240.921.6016.1015.91Of 14.56.
III29044.492.56-20.7315.67With15H10N6O4S244.772.50-20.8815.94
IV22043.312.248.3019.6 15.04With15H9lN6O3S2At 42.812.168.4219.9715.24
V30044.992.90-At 24.4815.56C15H11N7O3S244.882.76-At 24.42At 15.97
VI30045.233.14-27.9015.89C15H12N8O2S244.993.02-27.9816.01
VII30045.672.688.9417.7516.22C15H10ClN5O2S245.982.579.0517.8716.37
VIII30046.022.95-20.0315.24C16H12N6O4S246.152.90-20.1815.40
IX26547.903.41-19.4314.69 Cl7H14N6O4S247.433.28-19,5214.90
X26042.872.16-18.3317.95With19H11N7O6S343.102.09-18.5218,17
XI29046.132.51-17.7716.29C15H9N5O4S246.512.34-18.0816.55
XII30044.282.49-17.0415.61C15H9N5O5S244.662.25-17.3615.90
XIII23042.222.874.0418.0114.87C30H22ClN11O9S4At 42.682.634.2018.2515.19
XIV230At 43.143.16-20.1515.33With30 H24N12O9S4At 43.682.93-20.3815.55
XV23044.362.99-18.9315.68With30H23N11O9S444.492.86-19.0315.84

B. EXPERIMENTAL DETERMINATION of the BIOLOGICAL PROPERTIES of the CLAIMED COMPOUNDS.

Example 11. Determination of the effect on the herpes simplex virus.

Antiviral activity was studied in relation to herpes virus type I (HSV - I/ Leningrad/248/88) by the conventional method [24 - Gentry G.A. and other J. of Clinical Microbiology, 1985, 22, 2, RI 99-204]. Viruses were grown on transplantable cell culture Vero obtained from the Bank of cell cultures at the Institute of Cytology of the Russian Academy of Sciences.

Table 3.

The action of the claimed compounds on herpes simplex virus.
NNConnection100*The number of cells 50:10*
1Acyclovir**-9600***(80%)****
2DMCO100001000010000
3 Control cells100001000010000
4la10800(90%)9600(80%)7200(60%)
5lib12000(100%)10800(90%)8400(70%)
6III12000(100%)9600(80%)8400(70%)
7IV9600(80%)8400(70%)6000(50%)
8V10800(90%)9600(80%)7200(60%)
9VI12000(100%)10800(90%)8400(70%)
10VII8400(70%)6000(50%)4000(30%)
11VII9600(80%)8400(70%)6000(50%)
12IX9600(80%)8400(70%)6000(50%)
13X10800 (90%)9600 (80%)7200 (60%)
14XI9600 (80%)8400 (70%)6000 (50%)
15XII6000 (50%)3600 (30%)1200(10%)
16XIV9600 (80%)8400 (70%)6000 (50%)
* Concentration of the claimed compounds (mg/l)

** - the drug in this concentration was not investigated.

*** the number of cells in 100 fields of view,

**** the percentage protection of cells from infection

The results in table 3 show that the claimed compounds possess activity against herpes virus.

Example 12. Defining actions for Chlamydia trachomatis

Antimicrobial activity of the claimed compounds was studied in relation to .trachomatis D323-standard strains from the collection of Department of Microbiology, St. Petersburg State Medical University. AK. Pavlov. This strain, isolated from a patient with chlamydial urethritis is the morphology and physiological activity typical representatives of this species, sensitive to the action of drugs used for the treatment of chlamydial infection.

The effectiveness of the drugs was assessed by protecting cells Msso and L929, during infection with chlamydia at a concentration of 1·106cells/ml [25, 26 - Judson VA and other J. of Clinical Microbiology, 1988, vol.26, N12, R-2658; Fenelon LE, etc. J of Antiimcrobial Chemotherapy, 1990, 26, R-767]. Evaluation of the results was performed by identifying chlamydial cytoplasmic inclusions method immunofluorescence (MicroTrac Chlamydia trachomatis Direct Specimen Test) and chlamydial antigens method CylaMonoScreen (Russian-British Joint Venture 66 Regent's Pare Road London N1 7SX) [26 - Fenelon LE and others J. of Antimicrobial Chemotherapy, 1990, 26, R-767].

The effect of the drug was determined by analyzing the state of the monolayer and the number of cells with CAI compared with the control (cell culture infected with C.trachomatis D323), took into account the number of unchanged cells in 100 fields of view obtained using a special grid eyepiece of the microscope.

60
Table 4.

The action of the claimed compounds for C.trachomatis.
NNConnectionThe percentage protection of cells from chlamydia, %
  100*30*
1.Ib8060
2.Iia9070
3.III10070
4.IV8050
5V8050
6VI8050
7VII9050
8VIII9070
9IX8050
10X100
11XI9050
12XII6040
13.XIII8060
* Concentration of the claimed compounds (mg/l)

The obtained data testify that investigated the claimed compounds can be used for the treatment of diseases caused by chlamydia.

Example 13. Activity against influenza viruses.

Determination of antiviral activity of compounds against influenza virus was performed on the model of the chorion allantoine shell (HAO).

Compounds in the tested concentrations was dissolved in the medium for HAO and added into the wells of panels with fragments HAO, then added the virus, and incubated at a temperature of 33-34°48 (influenza type a) and 72 (influenza type b) hours. Virusinghviru action of these compounds was evaluated by the reaction of haemagglutination (DSA) adding 1% chicken erythrocytes in the culture fluid.

The effectiveness of the compounds was assessed by the reduction of infectious virus activity in experience compared to control - index neutralization (JN). When set to 1.0 IN the drug is considered inactive when YING from 1.0 to 2.0, when YING above a 2.0 active.

The titer of the virus was calculated by the method of R. the Yes and Mana.

Table 5.

The activity of the claimed compounds against influenza viruses.
ConnectionThe neutralization index
Influenza virus aInfluenza virus
IB0.50,5
Iia1,51,5
III0.51,0
IV2,01,5
V1,01,5
VI201,5
VII2,01,5
VIII2,01,5
IX2,01,5
X1,51,0
XI1,51,5

Thus, the claimed compounds possess activity against influenza viruses a and B.

Example 14. Activity against human immunodeficiency virus. Activity against the human immunodeficiency virus was identified for the protection of T lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27. Cells infected with the virus, were analyzed by 1) indirect immunofluorescence (IFA) polyclonally polerowanie anticorodal from HIV-infected and AIDS patients (titer antibodies in ELISA is 1:1000000). In the tests used a dilution of 1:40. 2) In a competitive ELISA with monoclonal antibodies (nb) to P24 HIV and polyclonal substrate. As a control used azidothymidine (AZT) (Sigma).

Table 6.

Anti-HIV activity of the claimed compounds.
SubstanceConcentrationThe level of inhibition of virus reproduction (in %)
I100 mg/l100
50 mg/l90
5 mg/l70
III100 mg/l100
50 mg/l90
5 mg/l70
V100 mg/l100
50 mg/l100
5 mg/l90
XIV100 mg/l100
50 mg/l100
5 mg/l100
XV100 mg/l100
50 mg/l100
5 mg/l90
Control (AZT)100 mg/l100
50 mg/l100
5 mg/l 100

Thus, the tested samples inhibit the reproduction of human immunodeficiency virus 1.

Example 15. The use of the claimed compounds together with drugs used to treat AIDS.

The combined effect was assessed by protecting cells while adding test substances and azidothymidine. Activity was determined for the protection of T lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27. Cells infected with the virus, were analyzed by 1) indirect immunofluorescence (IFA) with polyclonal polerowanie anticorodal from HIV-infected and AIDS patients (antibody titer

ELISA is 1:1000000). In the tests used a dilution of 1:40. 2) In a competitive ELISA with monoclonal antibodies (nb) to P24 HIV and polyclonal background.

Table 7.

The inhibition of the reproduction of the HIV virus
SubstanceConcentration, mg/lThe level of inhibition of virus reproduction (in %)
1b5.070
0,520
AZT5.0100
0,0550
Ib+AZT0,5+0,05100
XIV5100
0.560
Ib+AZT0,5+0,05100

The results show that the inventive compounds may be used in conjunction with standard drug azidothymidine used for the treatment of AIDS.

Example 16. Determination of acute toxicity of the inventive compounds compound was administered via the mouth using a gastric probe (1000 mg/kg) or intraperitoneally (200 mg/kg) nonlinear white mice weighing 20-25 g (5 males and 5 females in each of the tested groups), and then watched their condition for 14 days. The absence of symptoms characteristic of toxic effects, and no animals died during a specified period of time allows us to conclude that within the studied doses of substances do not exhibit acute toxicity used in the model.

Industrial applicability

Examples 1-8 practical synthesis and chemical-physical analysis of the claimed compounds listed in tables 1 and 2 show the possibility of laboratory and industrial synthesis of all the claimed compounds means mastered the modern pharmaceutical industry, as well as their clear identification of common methods of control.

A series of the above experiments by definition is the biological properties showed that the claimed compounds possess biological activity against various microorganisms, especially viruses, HIV, herpes, influenza a and b), indicating the possibility of their use in the treatment of various viral infections caused by DNA viruses (herpes simplex virus) and RNA (influenza viruses and HIV), and some bacterial diseases caused by chlamydia. On the basis of the obtained compounds can be created pharmaceutically acceptable compositions and modifications compatible with drugs and delivery systems for drugs, providing maximum system circulation active component in plasma. The main route of administration is intravenous. However, there may be other methods used in the introduction, to ensure the delivery of active component in the systemic circulation is subcutaneous, intramuscular, inhalation, intraperitoneal, and other Doses and modes of introduction for this are determined by the nature of the used active ingredient, will depend on the route of administration.

The results obtained indicate the achievement of the objectives of the invention is synthesized derivatives of 2.8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues. For the synthesis of the claimed compounds used new technology is GII, as described in the application. Thus, in our opinion, the proposed drug (new substances) satisfy all the requirements of the invention: they are new, non-obvious and industrially applicable.

1. A substance having antiviral and antibacterial activity based on the derivatives of 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, characterized in that it includes 5 derives the specified group of General formula A1*M:

where X is selected from the group: O, NH, N-Alkyl;

R1 is selected from the group: H, HE, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar. N(Alkyl)2, SH, S-Alkyl, S-Ar, S-Hetaryl;

R2 is selected from the group of C6H5, Aryl;

R3 is selected from the group: H, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar, S-Hetaryl;

M is absent or selected from the group of cations Na, K, Li, ammonium, or any other pharmacologically acceptable cation; or a complex pharmacologically acceptable cation (see above) with the anion of one of the derivatives of A1 (options R1-R3 defined above).

2. The substance according to claim 1, wherein X=O, R1=OH, R2=C6H5, R3=Cl, M is absent (Ia).

3. The substance according to claim 1, wherein X=O, R1=OH, R2=C6H4-4-NO2, R3=Cl, M none (Ib).

4. The substance according to claim 1, wherein X=O, R1=R3=Cl, R2=C6H4-4-NO2M no (IIA).

5. The substance according to claim 1, characterized who eat that X=O, R1=OH, R2=C6H4-4-NR2, R3=NH2M no (III).

6. The substance according to claim 1, wherein X=O, R1=Cl, R2=C6H4-4-NO2, R3=NH2M no (IV).

7. The substance according to claim 1, wherein X=O, R1=R3=NH2, R2=C6H4-4-NO2M no (V).

8. The substance according to claim 1, wherein X=NH, R1=R3=NH2, R2=C6H4-4-NO2M no (VI).

9. The substance according to claim 1, wherein X=NH, R1=OH, R2=C6H4-4-C1, R3=NH2M no (VII).

10. The substance according to claim 1, wherein X=O, R1=OH, R2=C6H4-4-NO2, R3=NHCH3M no (VIII).

11. The substance according to claim 1, wherein X=O, R1=OH, R2=C6H4-4-NO2M no (IX).

12. The substance according to claim 1, characterized in that

13. The substance according to claim 1, wherein X=O, R1=OH, R2=C6H4-4-NO2, R3=H, M no (XI).

14. The substance according to claim 1, wherein X=O, R1=R3=OH, R2=C6H4-4-NO2M no (XII).

15. The substance according to claim 1, wherein X=O, R1=OH, R2=C6H4-4-NO2, R3=Cl, M=NH3+Al according to claim 1, where X=O, R1-R3=OH, R2=C6H4-4-NO2(XIII).

16. The substance according to claim 1, wherein X=O, R1=OH, R2=C6H4-4-NO2, R3=NH2M=NH3+Al according to claim 1, where X=O, R1=R3=OH, R2=C6H4-4-NO2(XIV).

17. Substances who according to claim 1, wherein X=O, R1=OH, R2=C6H4-4-NO2, R3=H, M=NH3+Al according to claim 1, where X=O, R1=R3=OH, R2=C6H4-4-NO2(XV).



 

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--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine
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