Tri-indolylmethane derivatives substituted in indole nucleus, method of obtaining said compounds and antibacterial and antifungal activity thereof

FIELD: chemistry.

SUBSTANCE: invention relates to the novel tri-indolylmethane derivatives of general formulae I and II. The compounds can be used during bacterial or fungal infection and for protecting different products from harmful effect of bacteria or fungi, particulary as antiseptics or for disinfection. In general formulae

I

or II , where R1; R7; R13 independently represent hydrogen, alkyl, substituted alkyl, R2; R8; R14 independently represent hydrogen, alkyl, substituted alkyl, -OH, -OR, C1-C4acyl, where R is alkyl or substituted alkyl, R3-R6; R9-R12; R15-R18 independently represent hydrogen, alkyl, substituted alkyl, -OH, -OR, C1-C4acyl, where R represents alkyl or substituted alkyl, Y is an anion of a pharmacologically acceptable organic or inorganic acid; R19 is hydrogen, alkyl, substituted alkyl acyl, metal ion. The invention also relates to methods of obtaining compounds of formulae I and II, a pharmaceutical composition and use. The invention relates to a method for synthesis of tri-indolylmethane of formula III mono-substituted in the methane group which is an intermediate compound.

EFFECT: obtaining tri-indolylmethanes of general formulae I or II having antibacterial and antifungal activity.

17 cl, 4 dwg, 4 tbl, 5 ex

 

The invention relates to new derivatives of triandayllidou substituted in the indole nucleus, corresponding to the General formula I or II, having antibacterial and antifungal activity, as well as pharmaceutical compositions and methods of producing and inhibition. The creation of new medicinal compounds and products based on them, acting on gram-positive and gram-negative pathogens remains highly relevant in the context of rapid development of bacterial resistance to existing drugs. In recent years, from the blood of patients excreting strains of pathogenic bacteria that are resistant not only to beta-lactams 3rd generation, but also to fluoroquinolones, aminoglycosides, vancomycin. No less urgent search for new compounds with antifungal activity, since the use of macrolide lactones type of amphotericin b is complicated by the high toxicity of these compounds. Also widely used at present antifungal compounds derived heterocycles is a rapidly developing drug resistance. Especially fast and dangerous is the development and dissemination of bacteria and fungi with drug resistance in a hospital setting, and treatment of hospital infections that are resistant to existing drugs, there is a need for the tons of new drugs with a new mechanism of action.

Known derived triandayllidou allocated in the process of growing genetically modified strain of E. coli with artificially integrated in its chromosome 24546-membered metagenomic fragment constructed from DNA extracted from soil bacteria. This derivative corresponding to the formula I, where R1-R18=H, called turbomachine A. However, the connection has a low antibacterial activity against gram-negative and gram-positive microorganisms in vitro [Gillespie D.E.; Brady S.F.; Bettermann and others. Applied and Environmental Microbiology; Sept. 2002, p.4301-4306].

The closest connection to the compounds of the present invention described in the patent application U.S. 20010047029. The compounds are derivatives of three(indol-3-yl)matilija substituted in the benzene nuclei, and have a low antibacterial and antifungal activity. All known compounds described in this patent do not contain substituents at the nitrogen atom of indole nuclei. Compounds of the present invention of the formula I or II (salt triangularmatrix and friendlycare) in contrast to the known compounds have at least one or more indole nuclei with substituent on the nitrogen atom of indole cycle. The introduction of such substituent allows to achieve antibacterial and antifungal activity, much higher than opican the e analogues.

Known methods for producing derivatives of triandayllidou (salts triangularmatrix) by oxidation of the corresponding industeries of triandayllidou various oxidants, such as dicyandiamide or chloranil [Gillespie D.E.; Brady S.F.; Bettermann and others. Applied and Environmental Microbiology; sept. 2002, p.4301-4306; Budzikiwicz H., H.Eckau and M.Ehrenberg, Tet. Lett., 1972, 36, p.3807-3810]; trityl the perchlorate [Stupnikova, .V.; Rybenko, L.A.; Skorobogatova Z.M.; Sheinkman A.K.Khim. Geterotsikl. Soedin. 1978, 416]; FeCl3[Muller J.; Pindur, U.Arch. Pharm. 1984, 317, 555-561] and a number of other Proposed according to the present invention, the method of oxidation triandayllidou resulting salts triangularmatrix, enables to reduce the cost and simplify the procedure of oxidation, separation and purification of the latter, to avoid the use of expensive and toxic chemicals polluting the environment.

Known methods for producing original triandayllidou condensation of the corresponding indoles with intellegible in terms of catalysis triflate lanthanides [Chen U.S.; L. Yu; Wang, P.G. Tetrahedron Letters 1995, 26, 4467], catalysis weak acids, for example acetic acid [J.Bergmann, J.Heterocyclic Chem., 1971, 8,329; Budzikiwicz H., H.Eckau, and M.Ehrenberg, Tet. Lett., 1972, 36, p.3807-3810; Jun Li, Bing Guang and others Heterocycles, 2003, Vol 60, No 6; 1307-1315], slightly clay Montmorillonite K-10 [M. Chakrabarty and S. Sarkar, Tet. Lett, 2002,43, str-1353] and a number of others in Accordance with the present invention is a method of obtaining the source triandayllidou, which then applies the are to get the claimed compounds of the invention, has no analogues in contrast to known methods allows to obtain products with high yield, fast to develop libraries of compounds for screening and get in some cases asymmetrical triangularmatrix inaccessible by other methods.

According to the present invention provides compounds corresponding to formulas I or II

where R1; R7; R13are independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci. Thus, it is mandatory that at least one of the substituents R1; R7; R13must be different from N.

R1; R7; R14are independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci; halogen, -OH, -OR, =O,- COOH, -COOR; -NH2, -N(R)2; -N+(R)3,CN,, -SO2R, -SOR,-CRO, acyl, carbarnoyl, thiocarbamoyl, R; where R may be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci. Any of the substituents may in turn be substituted. The provision and quantity of any substituents can vary R3-R6; R9-R12; R15-R18are independently hydrogen, alkyl, aryl, GE is Eroare, cycloalkyl, heteroseksualci; halogen, -OH, -OR, -COOH, -COOR; -NO2, -NO, -NH2-The othera; -N(R)2; -N+R3, -CN, -SO2R, -SO2N(R)2; -SOR,-CRO, -O-Sug, -N-Sug, acyl, carbarnoyl, thiocarbamoyl, R; where R may be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci. Sug is any cyclic or acyclic carbohydrate. Any of the substituents may in turn be substituted. The provision and quantity of any substituents can vary;

Y-represents the anion of any pharmacologically acceptable organic or inorganic acids;

R19.represents hydrogen, alkyl, acyl, metal ion.

The above compounds of formula I or II include all stereoisomers - enantiomers or diastereoisomers (individual, racemates, enriched in one of the forms etc.) if the existence of such possible. The above compounds of General formula I or II include any aggregate state of these compounds - including amorphous form, crystalline form, solvate.

The above compounds of General formula I or II include any pharmacologically acceptable salt forms of the above, if the existence of such possible.

The AOC is e, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound corresponding to formula I or II in a mixture with at least one acceptable carrier.

The term "alkyl" refers to straight or branched, substituted or unsubstituted, saturated or unsaturated C1-C24hydrocarbon chain containing or not containing suitable heteroatoms. The number and position of unsaturated bonds and heteroatoms can vary. Heteroatoms independently can be selected from the group consisting of nitrogen atoms, oxygen, sulfur, phosphorus. The nature, number and position of substituents can vary. The substituents may be independently selected from the group consisting of-OH, -OR, -COOH, -COOR; -NO2, -NO, -NH2-The othera; -N(Ra)2; -N+(Ra)3, -CN, -SO2Ra, -SORa,-CRaO, -O-Sug,-N-Sug, acyl, carbarnoyl, thiocarbamoyl, halogen, Ra; where Ramay be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci. Sug is any cyclic or acyclic carbohydrate. Any of the substituents may in turn be substituted. The position and number of any of the substituents may vary.

The term "cycloalkyl" refers to feast upon the fair or unsaturated, substituted or unsubstituted monocyclic, bicyclic, tricyclic or macrocyclic3-C-24the hydrocarbon chain. The nature, number and position of substituents can vary. The substituents may be independently selected from the group consisting of-OH, -OR, -COOH, -COOR; -NO2, -NO, -NH2-The othera; -N(Ra)2;-N+R3, -CN, -SO2R, -SOR,-CRO, -O-Sug,-N-Sug, acyl, carbarnoyl, thiocarbamoyl, halogen, R; where R may be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci. Sug is any cyclic or acyclic carbohydrate, Any of the substituents may in turn be substituted. The position and number of any of the substituents may vary.

Examples of typical cycloalkyl can be cyclopropyl, cyclobutylmethyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclododecyl, bicyclopentyl, bicyclohexyl, bicycloheptene, substituted, bornyl, norbornyl and similar.

The term "heteroseksualci" refers to a saturated or unsaturated, substituted or unsubstituted monocyclic, bicyclic, tricyclic or macrocyclic C2-O-24hydrocarbon chain containing suitable heteroatom selected from S, O, N, or C. the Character, the number is the position of the substituents can vary. The substituents may be independently selected from the group consisting of-OH, -OR, -COOH, -COOR; -NO2, -NO, -NH2-The othera; -N(R)2; -N+R3, -CN, -SO2R, -SOR,-CRO, -O-Sug,-N-Sug, acyl, carbarnoyl, thiocarbamoyl, halogen, R; where R may be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci. Sug is any cyclic or acyclic carbohydrate. Any of the substituents may in turn be substituted. The position and number of any of the substituents may vary.

Examples of typical heterocyclization can serve piperazinil, piperidinyl, morpholinyl, hinokitiol, crown ethers, azacrown esters and the like.

The term "aryl" refers to a stable, saturated or unsaturated, substituted or unsubstituted, With6monocyclic ring; a stable, saturated or unsaturated, substituted or not substituted C12-C14articulated bicyclic ring; a stable, saturated or unsaturated, substituted or not substituted C12-C14articulated tricyclic ring; a stable, saturated or unsaturated, substituted or not substituted C14-C16articulated tetracyclic ring. Preferably the aryl is substituted by one or more residues. The nature, number and position for which estately can vary. The substituents may be independently selected from the group consisting of-OH, -OR, -COOH, -COOR; -NO2, -NO, -NH2-The othera; -N(R)2; -N+R3, -CN, -SO2R, -SOR,-CRO, -O-Sug,-N-Sug, acyl, carbarnoyl, thiocarbamoyl, halogen, R; where R may be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci. Sug is any cyclic or acyclic carbohydrate. Any of the substituents may in turn be substituted. The position and number of any of the substituents may vary.

Examples of typical arrow can serve as phenyl, biphenyl, naphthyl, fluorenyl and similar.

The term "heteroaryl" refers to a stable, saturated or unsaturated, substituted or unsubstituted C4-C7organic monocyclic ring having a heteroatom selected from S, O and N; a stable, saturated or unsaturated, substituted or not substituted C9-C10articulated bicyclic ring containing one or more heteroatoms selected from S, O and N; a stable, saturated or unsaturated, substituted or not substituted C12-C14articulated tricyclic ring, having one or more heteroatoms selected from S, O and n Atoms of nitrogen and sulfur in these rings can be oxidized, the nitrogen atom may be Quaternary. Before occhialino heteroaryl substituted by one or more residues. The nature, number and position of substituents can vary. The substituents may be independently selected from the group consisting of-OH, -OR, -COOH, -COOR; -NO2, -NO, -NH2-The othera; -N(R)2; N+R3, -CN, -SO2R, -SOR, -CRO, -O-Sug.-N-Sug, acyl, carbarnoyl, thiocarbamoyl, halogen, R; where R may be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci. Sug is any cyclic or acyclic carbohydrate. Any of the substituents may in turn be substituted. The position and number of any of the substituents may vary.

Examples of typical heteroaryl are indolyl, piperidyl, thienyl, pyridyl and the like.

The term "acyl" denotes a group corresponding to the formula: -COR, where R can be a substitute, choose from a number of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci.

The term "carbarnoyl" refers to the group corresponding to the formula-CON(R)2where R may be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heteroseksualci.

The term "thiocarbonyl" refers to the group corresponding to the formula:

-CSN(R)2where R may be the same or different substituents selected from the range of: hydrogen, alkyl, aryl, shall heteroaryl, cycloalkyl, heteroseksualci. The term "carbohydrate" refers to any cyclic or acyclic carbohydrate.

The term "halogen" means a fluorine radical, bromine, chlorine, iodine.

The term "stereoisomers" refers to the isomers, which differ in the spatial arrangement of the atoms. Stereoisomers that are incompatible mirror images of each other are called enantiomers or optical isomers. Stereoisomers that are not mirror images of each other are called diastereomers.

The term "Pharmaceutically acceptable" means a group or compound that is used in obtaining pharmaceutical compositions and which are usually safe in biological or other respects, non-toxic and acceptable in veterinary medicine and in the pharmaceutical industry.

The term "Pharmaceutically acceptable salts" means salts that are pharmaceutically acceptable and have appropriate pharmacological activity of the parent compound. Such salts include salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid, etc. or salts of organic acids such as formic, acetic, propionic, benzoic, benzolsulfonat, tawasul the background, econsultancy, methansulfonate, camphorsulfonate, succinic, fumaric, maleic, lactic, malic, almond, tartaric, citric, gluconic, glucuronic, glycolic, salicylic, trimethyllysine, etc. Assumes that all farmatsevticheskii acceptable salts include solvate or crystalline form of the specified salt. The term "solvate" means a solvated form, containing stoichiometric or non-stoichiometric amount of solvent.

The present invention also relates to a method of producing substances corresponding to the formula I by oxidation of the corresponding triandayllidou.

The method includes the following steps:

the dissolution or dispersion of the original triandayllidou in organic or inorganic solvents with the addition of the acid corresponding to the received salt, or

dissolving or dispersing triandayllidou directly in the acid corresponding to the received salt.

Then this solution or dispersion is brought into contact with oxygen or oxygen-containing gas mixtures, or solutions containing dissolved oxygen, in the presence or in the absence of substances that increase the surface of contact between liquid and gaseous phase, such as, for example, activated carbon, or other substances and conditions that the temperature is the solubility of oxygen in these environments. The product is then isolated in the form of a corresponding salt triangularmatrix. The method of obtaining compounds of the formula I, is carried out according to the scheme I:

The present invention also relates to a method for obtaining the corresponding compounds of formula II from compounds of the formula I (which in turn can be obtained as the above method, and any other known), treatment of the latter in dissolved or solid or molten state solution with pH>7, or fusion, or by the action of a solid salts of alkaline or alkaline earth metals, or the effect on them of basic salts or carbonates of metals or amines. The method is carried out according to scheme II:

The invention also relates to a method for obtaining compounds of the formula I from compounds of formula II (which in turn can be obtained as the above method, and any other known), processing them in a dissolved or solid or molten state solution with pH<7, or by the action of a liquid, solid or gaseous acids. The method is carried out according to scheme III:

The present invention relates to a method of obtaining from the dinani, the corresponding formula III (in which the values of R1-R18correspond to those of formula (I), which are used as starting substances for the synthesis of substances corresponding to formulas I and II. How is that not substituted in the 3-atom indoles with more electron-donating substituents in the nucleus substituents which increase the electron density on 3-C atom of indole cycle) substituted indoles with less electron-donating substituents in triangularmatrix under the action of weak acid catalysts and/or Lewis acids, when mixed components: with heating or without it, in a suitable solvent or in the melt. The best result was achieved by boiling in alcohol and used as catalysts lanthanide triflates. The method is carried out according to scheme IV:

Using this scheme, to create a number of derivatives can have only one primary representative of the series from which you can get further analogues of the simple effect of the substituted indoles (scheme IV).

The compound of formula III.

where R, R1'-substituents, in total or separately generates the electronic density of 3-atom of indole cycle less than R2'and R3'cumulatively or individually. And R is selected from alkyl or for EDINOGO of alkyl, R1'selected from hydrogen and alkyl, R2'means alkyl or substituted alkyl, R3'has values of R3-R6,R9-R12, R15-R18.

The invention relates also to a method of inhibiting the activity of gram-positive and gram-negative microorganisms introduction of pharmaceutically effective amounts of the compounds corresponding to formulas I or II, or a pharmaceutical composition containing a therapeutically effective amount of at least one compound corresponding to formula I or II in a mixture with at least one acceptable carrier or solvent.

The method of introduction may be made to a person or animal suffering from a bacterial infection, one of the currently known methods (for example, topically, orally, intravenously, intramuscularly, and others)

The invention relates to a method of inhibiting the reproduction of pathogenic bacterial microflora on the environmental objects or materials subject to the destructive effects of bacterial microflora (e.g. conservation), including the processing of these objects, for example for the purposes of antiseptics and disinfectants, or materials, for example, to conserve an effective amount of the compounds corresponding to formulas I or II, or a composition comprising effectiveagainst at least one connection corresponding to the formula I or II in a mixture with at least one acceptable carrier or solvent.

The invention relates to a method of inhibiting fungal activity involving the introduction of a pharmaceutically effective amount of the compounds corresponding to formulas I or II, or a pharmaceutical composition containing a therapeutically effective amount of at least one compound corresponding to formula I or II in a mixture with at least one acceptable carrier or solvent.

Introduction you can perform one of the currently known methods (for example, topically, orally, intravenously, intramuscularly, and others) to a person or animal suffering from a fungal infection.

The invention relates to a method of inhibiting the activity of pathogenic fungal microflora on environmental objects or materials subject to the destructive effects of fungal microflora, including the processing of these objects, for example for the purposes of antiseptics and disinfectants, or materials, such as conservation, an effective amount of the compounds corresponding to formulas I or II, or a composition comprising an effective amount of at least one compound corresponding to formula I or II in a mixture with at least one acceptable carrier or solvent.

The invention also relates to the means of representing triangularmatrix General formula I or II according to claim 1 as an antibacterial or antifungal agent prevents the growth of pathogenic bacterial or fungal microflora, or as an antibacterial agent against gram-positive and gram-negative bacteria and as an antifungal agent. Typical compounds according to the invention are given in tables I and II, where for each compound corresponding to the formula I, stated molecular weight according to mass spectrometry (method ionization, MALDI, the device MALDI TOF Bruker BIFLEX III), and compounds of the formula II, shows the spectra of nuclear magnetic resonance (1H NMR, 400 MHz, solvent DMSO-d6the device Varian Unity 400)

Table I
mass spectra typical of the obtained compounds corresponding to the formula I.
substancemass spectrum
Calculated: Mw=539,22
LCTA-1293Mwcation:: 444,24
metasolv is at Tris(1-ethyl-1H-indol-3-yl)matilija Found: 444.6 [M+]
Calculated: Mw=581,27
Mwcation: 486,29
LCTA-1319Found: 486.68 [M+]
methanesulfonate Tris(1-propyl-1H-indol-3-yl)matilija
Calculated: Mw=623,32
LCTA-1574Mwcation: 528,34
methanesulfonate Tris(1-butyl-1H-indol-3-yl)matilijaFound: 528,64 [M+]
Calculated: Mw=665,37
M^ucation: 570,38
LCTA-1578Found: 570,38 [M+]
methanesulfonate Tris(1-pentyl-1H-indol-3-yl)matilija

Calculated: Mw=707,41
Mwcation: 612,43
Nai is prohibited: 612.92 [M +]
LCTA-1340
methanesulfonate Tris(1-hexyl-lH-indol-3-yl)matilija
Calculated: Mw=725,27
Mwcation: 630,29
Found: 630,41 [M+]
LCTA-1575
methanesulfonate Tris(1-benzyl-1H-indol-3-yl)matilija
nCalculated: Mw=875,6
Mwcation: 780,62
Found: 780,83 [M+]
LCTA-1576
methanesulfonate Tris(1-decyl-lH-indol-3-yl)matilija

Calculated: Mw=683,15
methanesulfonate Tris(5-chloro-1-propyl-1H-indol-3-yl)matilijaMwcation: 588,17
LSN-89Found: 588,38 [M+]
Calculated: Mw=593,29
acetate Tris(5-methoxy-1-ethyl-1H-indol-3-yl)matilijaMwcation: 534,28
LSN-90Found: 534,39 [M+]
Calculated: Mw=545,3
acetate Tris(6-methyl-1-ethyl-1H-indol-3-yl)matilijaMwcation: 486,29
LSN-91Found: 486,31 R^G]
Calculated: Mw=567,26
methanesulfonate (1H-indol-3-yl)bis(2-methyl-1-propyl-1H-indol-3-yl)matilijaMwcation: 472,28
LCTA-1376Found: 472.03 [M+]

Table II
The spectra of nuclear magnetic resonance (1H NMR, 400 MHz, solvent DMSO-d6) typical of the obtained compounds corresponding to the formula II
1.23 (N; m); 4.09(6N; m); 5.70 (1H; s); 6.82(3H, t); 6.97 (3H; s); 7.03 (3H, t); 7.36 (3H, d); 7.49 (3H; d)
Tris(1-ethyl-1H-indol-3-yl)methanol
LCTA-1588
0.94 (N; m); 1.65 (6N; m); 4.08(6N; m); 5.69 (1H; s); 6.77 (3H, t); 6.90 (3H; s); 7.01 (3H, t); 7.36 (3H, d); 7.49 (3H; d)
Tris(1-propyl-1H-indol-3-yl)methanol
LCTA-1617
0.83 (N; m); 1.16 (6N; m); 1.65 (6N; m); 4.08(6N; m); 5.69 (1H; s); 6.77 (3H, t); 6.90 (3H; s); 7.01 (3H, t); 7.36 (3H, d); 7.49 (3H; d)
Tris(1-butyl-1H-indol-3-yl)methanol
LCTA-1589

0.85 (N; m); 1.14 (6N; m); 1.23 (6N; m); 1.65 (6N; m); 4.09(6N; m); 5.70 (1H; s); 6.77 (3H, t); 6.91 (3H; s); 7.01 (3H, t); 7.36 (3H, d); 7.49 (3H; d)
Tris(1-pentyl-1H-indol-3-yl)methanol
LCTA-1590
0.87 (N; m); 1.14 (6N; m); 1.23 (6N; m); 1.34(6N; m); 1.68 (6N; m); 4.09(6N; m); 5.70 (1H; s); 6.77 (3H, t); 6.91 (3H; s); 7.01 (3H, t); 7.36 (3H, d); 7.49 (3H; d)
Tris(1-hexyl-1H-indol-3-yl)methanol
LCTA-1618
1.25 (N; m); 4.11 (6N; m); 5.73 (1H; s); 6.82 (3H, t); 6.97 (3H; s); 6.93 (3H; d); 7.06 (3H; dd); 7.29 (3H; d)
Tris(5-chloro-1-ethyl-lH-indol-3-yl)methanol
LSN-94
1.23 (N; m); 3.71 (N; s); 4.10 (6N; m); 5.70 (1H; s); 6.69 (3H; dd); 6.88 (3H, d); 6.97 (3H; s); 7.25 (3H; d)
Tris(1-ethyl-5-methoxy-1H-indol-3-yl)methanol
LSN-95

0.82 (6N; t); 1.67(4H, m); 2.19 (6N; s); 4.06 (4H, t); 6.13 (1H; s); 5.67 (1H; s); 6.69 (2H; t;); 6.79 (1H, t); 6.93 (2H; t); 7.02 (3H, m); 7.13 (1H, d); 7.33 (2H, d); 7.37 (1H, d); 10.56 (1H; s)
(1H-indol-3-yl)bis(2-methyl-1-propyl-1H-indol-3-yl)methanol
LCTA-1619

Examples

Examples are given to provide an opportunity for the specialist in this area to learn more about the invention and its use in practice. Examples are given to illustrate and not limit the scope of the invention.

Stage I

Getting triandayllidou (substances corresponding to formula III and which is the source for the synthesis of substances is of oral I and II)

Source triangularmatrix can be obtained as described in the literature methods (examples 1 and 2), and proposed in the present invention method (example 3).

Tris-(1-ethyl-1H-indol-3-yl) methane (example 1) [Chen, U.S.; Yu, L.; Wang, P.G. Tetrahedron Letters 1995, 26, 4467]

To a mixture of 1-ethylindole (2.9 g, 20 mmol) and 1-ethyl-3-formylindole (1.73 g, 10 mmol) in ethanol (50 ml) was added 50 mg of La(OTf)3and boiled under reflux for 3 hours, after cooling to room temperature, the precipitation was filtered off, washed with 50 ml of ethanol, dried and obtained 4.25 g of Tris-(1-ethyl-1H-indol-3-yl) methane (yield 95%) as a colourless solid.

The same method can be obtained from the corresponding indoles and formylindolo:

Tris(1-methyl-1H-indol-3-yl)methane,

Tris(1-propyl-1H-indol-3-yl)methane,

Tris(1-butyl-1H-indol-3-yl)methane,

Tris(1-pentyl-1H-indol-3-yl)methane,

Tris{1-hexyl-1H-indol-3-yl)methane,

Tris(1-benzyl-1H-indol-3-yl)methane,

Tris(1-decyl-1H-indol-3-yl)methane,

Tris(1-propyl-5-chloro-1H-indol-3-yl)methane,

Tris(1-propyl-5-methoxy-1H-indol-3-yl)methane

Tris{1-propyl-6-methyl-1H-indol-3-yl)methane

(1H-indol-3-yl)bis(2-methyl-1-propyl-1H-indol-3-yl)methane

Tris-(1-ethyl-1H-indol-3-yl)methane (example 2) [Jun Li, Bing Guang and others Heterocycles, 2003, Vol. 60, No 6; 1307-1315]

A mixture of 1-ethylindole (2.9 g, 20 mmol) and 1-ethyl-3-formylindole (1.73 g, 10 mmol) in acetic acid (0 ml) with addition of acetic anhydride was heated under reflux for 2 hours, after cooling to room temperature, poured into water, the precipitated residue was filtered off, washed with 50 ml of ethanol, dried, and received 4.23 g of Tris-(1-ethyl-1H-indol-3-yl) methane (yield 95%) as a colourless solid.

The same method can be obtained from the corresponding indoles and formylindolo:

Tris(1-methyl-1H-indol-3-yl)methane,

Tris(1-propyl-1H-indol-3-yl)methane,

Tris(1-butyl-1H-indol-3-yl)methane,

Tris(1-pentyl-1H-indol-3-yl)methane,

Tris(1-hexyl-1H-indol-3-yl)methane,

Tris(1-benzyl-1H-indol-3-yl)methane,

Tris(1-decyl-1H-indol-3-yl)methane,

Tris(1-propyl-5-chloro-1H-indol-3-yl)methane,

Tris(1-propyl-5-methoxy-1H-indol-3-yl)methane,

Tris(1-propyl-6-methyl-1H-indol-3-yl)methane.

Tris-(1-ethyl-1H-indol-3-yl)methane (example 3)

To a mixture of Tris(1-methyl-1H-indol-3-yl)methane (4 g, 10 mmol) (obtained, for example, by the method described in example 1 or 2) and 1-ethylindole (4.35 g, 30 mmol) in ethanol was added 100 mg of La(OTf)3and boiled under reflux for 4 hours, after cooling to room temperature, the precipitation was filtered off, washed with 50 ml of ethanol, dried and obtained 4.25 g of Tris-(1-ethyl-1H-indol-3-yl) methane (yield 95%) as a colourless solid.

The same method can be obtained from Tris(1-methyl-1H-indol-3-yl)methane and the corresponding source of indoles:

Tris(1-propyl-1H-indol-3-yl)meta is,

Tris(1-butyl-1H-indol-3-yl)methane,

Tris(1-pentyl-1H-indol-3-yl)methane,

Tris(1-hexyl-1H-indol-3-yl)methane,

Tris(1-benzyl-1H-indol-3-yl)methane,

Tris{1-decyl-1H-indol-3-yl)methane,

Tris(1-propyl-5-chloro-1H-indol-3-yl)methane,

Tris(1-propyl-5-methoxy-1H-indol-3-yl)methane,

Tris(1-propyl-6-methyl-1H-indol-3-yl)methane,

(1H-indol-3-yl)bis(2-methyl-1-propyl-1H-indol-3-yl)methane.

Stage II

Tris-(1-ethyl-1H-indol-3-yl)matilija methanesulfonate (example 4)

To a suspension of 4.45 g (10 mmol) of Tris-(1-ethyl-1H-indol-3-yl) methane in 100 ml of butanol was added 0.5 g of activated charcoal, then added 1.43 ml (20 mmol) of methanesulfonate and stirred under air for 2 hours, then was filtered coal, washed butanolic solution, 2 times with water, it was evaporated, triturated the residue with ether, was filtered, washed with ether, received 4.31 g of Tris-(1-ethyl-1H-indol-3-yl)matilija methansulfonate (exit 80%) as a red amorphous powder.

The oxidation of the corresponding triandayllidou received similar to the following methansulfonate:

methanesulfonate Tris(1-propyl-1H-indol-3-yl)matilija,

methanesulfonate Tris(1-butyl-1H-indol-3-yl)matilija,

methanesulfonate Tris(1-pentyl-1H-indol-3-yl)matilija,

methanesulfonate Tris(1-hexyl-1H-indol-3-yl)matilija,

methanesulfonate Tris(1-benzyl-1H-indol-3-yl)matilija,

methanesulfonate Tris(1-decyl-1H-indole-yl)matilija,

methanesulfonate Tris(1-propyl-5-chloro-1H-indol-3-yl)matilija,

methanesulfonate Tris(1-propyl-5-methoxy-1H-indol-3-yl)matilija,

methanesulfonate Tris(1-propyl-6-methyl-1H-indol-3-yl)matilija,

methanesulfonate (1H-indol-3-yl)bis(2-methyl-1-propyl-1H-indol-3-yl)matilija using this technique and its modifications, the use of other acids, can be obtained and other salts triangularmatrix.

Tris(1-ethyl-1H-indol-3-yl)methanol (example 5)

To a suspension of 5.4 g (10 mmol)methansulfonate Tris-(1-ethyl-1H-indol-3-yl)matilija in ethyl acetate (40 ml) was added a solution of NaHCO3(10 wt.%, 30 ml), incubated under stirring for 30 min, separated the organic layer was evaporated it and got Tris(1-ethyl-1H-indol-3-yl)methanol (4.5 g, yield 98%) as a pale yellow amorphous substance.

similarly received:

Tris(1-propyl-1H-indol-3-yl)methanol,

Tris(1-butyl-1H-indol-3-yl)methanol,

Tris(1-pentyl-1H-indol-3-yl)methanol,

Tris(1-hexyl-1H-indol-3-yl)methanol,

Tris(1-benzyl-1H-indol-3-yl)methanol,

Tris(1-decyl-1H-indol-3-yl)methanol,

Tris(1-propyl-5-chloro-1H-indol-3-yl)methanol,

Tris(1-propyl-5-methoxy-1H-indol-3-yl)methanol,

Tris(1-propyl-6-methyl-1H-indol-3-yl)methanol,

1H-indol-3-yl)bis(2-methyl-1-propyl-1H-indol-3-yl)methanol, using this technique and its modifications, the corresponding salts of triangularmatrix you can get and other trienda methanole.

Testing of biological activity.

1. Study of antibacterial activity of the samples.

Was determined antibacterial activity against gram-positive and gram-negative bacteria. To determine this activity used the method of serial dilution in broth Mueller-Hinton (supplier company Acumedia USA) to determine the minimum overwhelming concentration (MBC) on 96-well plates (according to the recommendations NCCLC: National standards Committee for clinical laboratory tests and to Guide experimental preclinical study of new pharmacological substances (Moscow, Izd-vo Remedium, 2000))

The initial substance was dissolved in distilled water at a concentration of 1 mg/ml was Titrated broth, started the titration with a concentration of 64 μg/ml with a further twofold dilutions. Each determination was carried out twice. As bacterial material in the work strains were used in the initial concentration of 106COE/ml:

1) gram-positive bacteria

Staphylococcus epidermidis

Staphylococcus Haemolyticus

Staphylococcus aureus

Enterococcus faecalis

Enterococcus faecium

2) gram-negative bacteria

Esherihia Coli

Salmonella typhimurium

Klebsiella pneumoniae

Pseudomonas aeruginosa

after incubation at 37°C for 24 hours produced the results. For the IPC took certainly the th concentration of the test substance (μg/ml), when that was visible delay the growth of microorganisms.

Data on the activity are shown in table III.

The determination of the activity of antifungal drugs

Materials and methods

Determination of antifungal activity

The activity of the tested compounds against yeast and imperfect fungi was determined in vitro using micromethod recommended by the National Committee for Clinical Laboratory Standards (NCCLS), described in the document M27-a and M38-a, respectively, for yeast [Reference method for broth dilution antifungal susceptibility testing of yeasts: Approved standard M27-A. NCCLS, Wayne, PA, USA, 1997] and filamentous fungi [Reference Method for Broth Dilution Antifungal Susceptibility Testing of Conidium-Forming Filamentous Fungi: Approved Standard M38-A. NCCLS, Wayne, PA, USA, 2002].

The environment and the buffer

The study used the medium RPMI 1640 with L-glutamine and phenol red, without sodium bicarbonate with the addition of 0.2% glucose (ICN Biomedicals Inc., Ohio, USA), buffered 0,165 M morpholinepropanesulfonic acid (MOPS; ACROS ORGANICS, New Jersey, USA), pH 7.0.

Antifungals

The test substance was dissolved in dimethyl sulfoxide (DMSO) with initial concentration of 1600 mcg/ml Of the original solution in the same solvent was preparing a dilution series (1600 to of 3.13 μg/ml). Then these dilution in DMSO was diluted 50 times (first 10 times, then 5 times) in STD is bound used to experience medium RPMI 1640. Later during the experiment (when mixed with inoculum of test organisms) they were subjected to a further two-fold dilution, and concentration of the solvent in the experiment was reduced to 1%. The final concentration of the tested drugs was from 16 to 0.03 μg/ml Solutions of the test drugs were prepared immediately prior to use.

Strains of microorganisms

To determine the activity of compounds were used the following yeast strains: Candida albicans ATCC 14053, Cryptococcus humicolus ATCC 9949, and imperfect fungi: Aspergillus niger ATCC 16404, Fusarium oxysporum VKM F-140 (=CMI, IMI 90473). The microorganisms were grown and kept on solid nutrient media (on potato agar) in the form of oblique bars, filled 50% solution of glycerol at -70°C. For short term storage of culture was placed on agar beveled poles at -4°C. the Yeast before use in the experiment were grown on agar Saburo within 24 hours at 35°C (Candida albicans) or within 48 hours at 25°C (Cryptococcus humicolus) to obtain fresh cultures. Mushrooms before use in the experiment were grown on potato agar for 7 days at 35°C (Aspergillus niger), or 2 days at 35°C, followed by cultivation for 5 days at 25°C (Fusarium oxysporum) for maximum sporulation. Immediately before the experiment to identify the activity of the studied drugs were preparing and sowing suspension (inoculum) test organisms.

Preparation of inoculum

For the yeast inoculum was prepared by suspension of the colonies cultures in sterile buffered saline (0,85% NaCl). The resulting suspension was actively shaken on a Vortex for 15 s, and the density of the suspension was brought to an optical density of 0.5 McFarland standard (equivalent to 1-5×106cells/ml). The original suspension of yeast cultures were diluted 1:1000 with standard medium (RPMI 1640) to obtain a suspension of inoculum. The latter contained twice the concentration of cells compared to the final concentration in the experience (1-5×103cells/ml).

For fungi the initial suspension was prepared by gently washing the surface of fungal colonies sterile 0,85% soleum buffer. For preparation of inoculum of Aspergillus niger colonies pre-moistened sterile 1% (weight/volume) solution of Tween 20. Ultimately, the active suspension was shaken on a Vortex for 15 s and filtered through a sterile 4-ply paper filter to separate the cells and obtain a spore suspension. The density of the latter was measured at 530 nm and summed up to 0,09-0,11 for Aspergillus niger and 0.15-0,17 for Fusarium oxysporum. The suspension was diluted 1:50 in a standard medium (RPMI 1640) to obtain a suspension of inoculum in excess of the final concentration in the experience of 2 times (0.4 to 5×104cells/ml).

The number of cells in the inoculum was verified by plating on agar Saburo and under the couple of grown colonies.

Experiment and evaluation results.

Experiments were performed in sterile 96-well flat-bottomed plates. For this purpose, the holes of each tablet was made first, 100 μl of solutions of a serial dilution of the test drugs (RPMI medium 1640, the content of DMSO was 2%, and then 100 μl of a solution of inoculum of the test culture. Each drug in the experiment was attended not less than three times. In the panel of the experiment as controls consisted of wells containing no test drugs.

The plates were incubated at 35°C (Candida albicans and fungi), or 25°C (Cryptococcus humicolus) without shaking. Evaluation of the growth of the cultures was performed visually, using 4-stage scale: 0 = optical transparency, a complete lack of growth, 1 = weak growth (25% of control levels), 2 = significant growth inhibition (50% of control levels), 3 = weak growth inhibition (75% of control levels), 4 = no inhibition of growth. Minimal inhibitory concentration (MIC) of antifungal drugs were read at 24 h of cultivation for Candida albicans, and Cryptococcus humicolus and 48 h of cultivation for Aspergillus niger and Fusarium oxysporum.

MBC was defined as the lowest concentration of drug that completely prevents the growth of the test organism (scale = 0). To detect subtle differences between drugs against fungi, in some cases, the IPC was estimated as the minimum is oncentration, which was supposed weak (25% of control levels), the growth of the test organism (scale = 1). Data on BMD are shown in table IV.

1. Compounds corresponding to formulas I or II


where R1; R7; R13are independently hydrogen, alkyl, substituted alkyl, provided that at least one of the substituents R1; R7; R13different from N, and provided that if R2-R7are independently hydrogen, then at least one of the substituents R1; R7; R13must be different from methyl;
R2; R8; R14are independently hydrogen, alkyl, substituted alkyl, -OH, -OR, WITH1-C4acyl, where R is an alkyl or substituted alkyl, R3-R6; R9-R12; R15-R18are independently hydrogen, alkyl, substituted alkyl, -OH, -OR, WITH1-C4acyl, where R is an alkyl or substituted alkyl, Y(-)represents the anion of a pharmacologically acceptable organic or inorganic acid;
R19represents hydrogen, alkyl, substituted alkyl acyl, metal ion, in the form of a solvate and a pharmaceutically acceptable salt.

2. Pharmaceutical composition, oblagayuschiesya or antifungal activity, containing a therapeutically effective amount of at least one compound corresponding to formula I or II according to claim 1 in a mixture with at least one acceptable carrier.

3. The method of obtaining compounds of the formula I according to claim 1, which consists in the fact that the method is conducted according to the scheme I

(in which the values of R1-R18, Y(-)correspond to those of the formulas I and II, respectively, specified in claim 1), comprising the following steps:
the dissolution or dispersion of the original triandayllidou in organic or inorganic solvents with the addition of the acid corresponding to the salt obtained either dissolving or dispersing triandayllidou directly in the acid corresponding to the received salt, and
oxidation by contacting the resulting solution or dispersion with oxygen or oxygen-containing gas mixture or solutions containing dissolved oxygen, the selection of the obtained product in the form of a corresponding salt triangularmatrix.

4. The method according to claim 3, wherein the process is conducted in the presence of substances that increase the surface of contact between liquid and gaseous phase, such as, for example, activated carbon, or of substances and conditions that enhance the solubility of oxygen in these environments.

5. Methods for the producing compounds corresponding to the formula II according to claim 1, of the compounds corresponding to formula I, by treatment of the latter solution with pH>7, or solid salts of alkaline or alkaline earth metals, and / or basic salts or carbonates of metals or amines according to scheme II

(in which the values of R1-R18, Y(-)correspond to those of the formulas I and II, respectively, specified in item 1).

6. The method of obtaining compounds of the formula I according to claim 1, of the compounds of the formula II by treatment of the latter solution with pH<7, or by the action of a liquid, solid or gaseous acid according to scheme III

(in which the values of R1-R18, Y(-)correspond to those of the formulas I and II, respectively, specified in item 1).

7. The method of obtaining compounds of the formula III

where each of R1, R7, R13is selected from alkyl or substituted alkyl, each of R2, R8, R14is selected from a hydrogen atom or alkyl, and each of the other R3-R6, R9-R12, R15-R18independently selected from hydrogen, alkyl, halogen, -OR,
With1-C4acyl,
where R represents alkyl,
namely, that of unsubstituted 3-atom is Holy with more electron-donating substituents in the nucleus (substituents, which increase the electron density on 3-C atom of indole cycle) substituted indoles with less electron-donating substituents in triangularmatrix under the action of weak acid catalysts and/or Lewis acids by mixing the components according to the following scheme IV:

where R is selected from alkyl or substituted alkyl, R1'selected from hydrogen and alkyl, R2'means alkyl or substituted alkyl, R3'has values of R3-R6, R1-R12, R15-R18above, with R and R1'cumulatively or individually create an electron density of 3-indole cycle less than R3'and R2'cumulatively or separately.

8. The method according to claim 7, characterized in that the process is carried out by heating in a suitable solvent or in the melt.

9. The method according to any of claims 7, 8, wherein the process is carried out at the boiling alcohols and using as catalysts lanthanide triflates.

10. A method of inhibiting the activity of gram-positive and gram-negative microorganisms introduction of a pharmaceutically effective amount of a compound corresponding to formula I or II according to claim 1, or a pharmaceutical composition according to claim 2, containing a therapeutically effective amount of at least one of the compounds according to stuudio the formula I or II. in a mixture of at least one acceptable carrier or solvent.

11. Method of inhibiting the reproduction of pathogenic bacterial microflora on the environmental objects or materials subject to the destructive effects of bacterial microflora, including the processing of these objects, for example, order antiseptic or disinfecting effective amount of a compound corresponding to formula I or II according to claim 1, or a composition according to claim 2, containing an effective amount of at least one compound corresponding to formula I or II, in a mixture with at least one acceptable carrier or solvent.

12. Method of inhibiting fungal activity involving the introduction of a pharmaceutically effective amount of a compound corresponding to formula I or II according to claim 1, or a pharmaceutical composition according to claim 2, containing a therapeutically effective amount of at least one compound corresponding to formula I or II, in a mixture with at least one acceptable carrier or solvent.

13. A method of inhibiting the activity of pathogenic fungal microflora on environmental objects or materials subject to the destructive effects of fungal microflora, including the processing of these objects, for example, order antiseptic and disinfecting effective amount of the compounds is Oia, corresponding to formula I or II according to claim 1, or a composition according to claim 2, containing an effective amount of at least one compound corresponding to formula I or II, in a mixture with at least one acceptable carrier or solvent.

14. The method of use of compounds corresponding to formula I or II according to claim 1, as antibacterial agents against gram-positive and gram-negative bacteria), including the introduction of, for example, topically, orally, intravenously, intramuscularly pharmaceutically effective amount of a compound corresponding to formula I or II according to claim 1, or a pharmaceutical composition according to claim 2, containing a therapeutically effective amount of at least one compound corresponding to formula I or II, in a mixture with at least one acceptable carrier or solvent.

15. The method of use of compounds corresponding to formula I or II according to claim 1, as a means of preventing the reproduction of pathogenic bacterial microflora on the objects of the external environment (for example, for the purposes of antiseptics and disinfectants), including the processing of these objects effective amount of the compounds corresponding to formulas I or II, or a composition according to claim 2, containing an effective amount of at least one compound corresponding to formula I or II, in a mixture with at least one PR is acceptable carrier or solvent.

16. The method of using compounds of formulas I or II, as antifungal agents, including the introduction of, for example, topically, orally, intravenously, intramuscularly, pharmaceutically effective amount of a compound corresponding to formula I or II according to claim 1, or a pharmaceutical composition according to claim 2, containing a therapeutically effective amount of at least one compound corresponding to formula I or II, in a mixture with at least one acceptable carrier or solvent.

17. The method of using compounds of formulas I or II, as a means of preventing the reproduction of pathogenic fungal microflora on the objects of the external environment (for example, for the purposes of antiseptics and disinfectants), including the processing of these objects effective amount of a compound corresponding to formula I or II according to claim 1, or a composition according to claim 2, containing an effective amount of at least one compound corresponding to formula I or II, in a mixture with at least one acceptable carrier or solvent.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula , where X, R1, R2, R3, R4 and R5 assume values given in the description and paragraphs of the formula of invention, and their pharmaceutically acceptable salts.

EFFECT: compounds have antagonistic activity on histamine receptor 3 (H3).

25 cl, 3 tbl, 215 ex

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives with formula I , where: Ra is H; C1-C4alkyl; one of Rb, Rc, Rd and Re is C1-C4alkyl, and the others are H; or Rb, Re, Rd and Re are all H; and R is a radical with formula (a), (b) and (c), presented in the claim.

EFFECT: compounds inhibit protein kinase C (PKC), which allows for their use in making a medicinal agent for treating or preventing diseases or disorders mediated by T lymphocytes and/or PKC, particularly during transplantation.

8 cl, 11 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new 3-amino-1-arylpropylindoles of formula I: or to its pharmaceutically acceptable salts, where: p is equal to 1 or 2; Ar means: indolyl, 2,3-dihydroindolyl, indazolyl, benzimidazolyl, benzofuranyl, and each can be substituted; R1 means: phenyl, naphthyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isoxazolyl, pyrazolyl, quinolinyl, aryl-C1-6alkyl where each can be substituted; C3-6cycloalkyl; branched C1-6alkyl; R2 and R3 each independently stands for: H, C1-6alkyl; OH-C1-6alkyl; benzyl; or R2 and R3 together with nitrogen atom whereto attached can form optionally substituted tetra-heptamerous ring, optionally with additional heteroatom chosen from N, O; Ra means H, C1-6alkyl; Rb means H, C1-6alkyl; OH; Rc and Rd each independently means H, C1-6alkyl; Or one of R2 and R3 together with one of Ra and Rb and atoms whereto attached can form penta- or hexamerous ring, optionally with additional heteroatom chosen from O, N; or one of R2 and R3 together with one of Rc and Rd together with atoms whereto attached, can form tetra-hexamerous ring, optinally with additional heteroatom chosen from O, N; Rc means H, C1-6alkyl; provided when p =1, Ra, Rb, Rc and Rd mean H, Ar means indole-1-yl and R1 means C6H5, then R2 and R3 do not mean CH3 and do not form hexamerous ring, and when Ar means indole-3-yl, p =1, Ra, Rb, Rc and Rd means H and R1 means C6H5-, 3-OCH3C6H5- then R2 and R3 do not mean simultaneously H, and when p =1, Ra, Rb, Rc and Rd mean H, Ar means indolyl and R1 means thienyl, pyridinyl, quinolinyl, then one of R2 and R3 means H, and another means C1-6alkyl where possible substitutes are presented in cl.1 of.

EFFECT: compounds express activity of double inhibition serotonin reuptake, possibility to use thereof in making a pharmaceutical composition and a medical product.

32 cl, 7 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: method of producing cyclopropyl-condensed inhibitors of dipeptidyl peptidase IV involves using BOC-protected amine with structural formula (3) , obtained through reductive amination of acid with formula (1) by treating the said acid with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified concentrate of phenyl alanine dehydrogenase and formate dehydrogenase (PDH/FDH) enzymes and without separation - by treating the obtained amine of formula (2) with ditertbutyl dicarbonate, obtaining BOC-protected amine.

EFFECT: cutting on costs.

13 cl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining catalyst of dehydrating 4,5,6,7-tetrahydroindole into indole. Described is catalyst of dehydrating 4,5,6,7-tetrahydroindole into indole containing nickel sulphide applied on aluminium oxide, catalyst being dopated with sodium and chlorine ions and contains 0.30-2.00% of nickel, 0.20-1.50% of sulphur, 0.10-0.20% of sodium, 0.20-1.00% of chlorine. Also described is method of obtaining catalyst which lies in impregnation of aluminium oxide with nickel salt with further processing with metal sulphide at room temperature in water medium in presence of hydrochloric acid and surface-active substance. Catalyst is isolated by filtration without further washing, dopating of catalyst takes place, and dopants are fixed by means of thermal processing.

EFFECT: increase of mechanical strength and activity of catalyst, as well as increase of its service life.

4 cl, 1 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: in acidified indanylamines of general formula (I) R1-R4 have values given in description, A represents CH2, CHOH, B represents CH2 and R5 represents aryl or heteroaryl group, possibly substituted with substituents, listed in description. Said compounds are useful in regulation of endothelial nitrogen oxide synthase (eNOS) and, therefore they can be useful for production of medications for treatment of stable and unstable angina pectoris, Prinzmetal's angina, acute coronary syndrome, impaired heart function, cardiac infarction, stroke, thrombosis, peripheral artery occlusive disease, endothelial dysfunction, atherosclerosis, hypertension, lung hypertension, symptomatic hypertension, renovascular hypertension, erectile dysfunction, diabetes or diabetes complications, nephropathy, retinopathy, limited memory function, limited learning ability.

EFFECT: increase of composition efficiency.

37 cl, 441 ex, 2 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to method for production of indolo-pyrrolo-carbazole derivative according to formula (I) , or its pharmaceutically acceptable salt, that have antitumour activity. Invention also relates to method for production of indole compound according to formula (XII) , or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, distinguished by conducting interreaction between compound with formula (XIII) , or its pharmaceutically acceptable salt, where R1 is definitely above, Ra and Rb are either separately C1-C7-alkyl, or together form C3-C6-alkylene group, and hydrogen gas at 1 to 5 atmospheres, in presence of hydrogenation catalyst (applied as novel catalyst as well), which consist of rhodium compound, metal compound, and optionally amine, in inert solvent at room temperature; the rhodium compound being 1 to 10% rhodium on carbon, aluminium oxide, calcium carbonate, or barium sulphate, and metal compound being nickel (II), iron (II), iron (III), cobalt (II), or cobalt (III). Method is also submitted for production of bis-indole compound by formula (VIII) , or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, Y is hydrogen, C1-C7-alkyl, phenyl, benzyloxymethyl, or C7-C12-aralkyl, consisting in reaction of indole compound by formula (XII), or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, with ethylmagnesium chloride, or butylmagnesium chloride, or magnesium compound by formula (X) RdMgRd, where Rd is butyl, in inert solvent, followed by conducting interreaction between product obtained and maleimide compound by formula (IX) , where X is halogen, and Y as above, in inert solvent.

EFFECT: improved method for indolo-pyrrolo-carbazole production.

15 cl, 68 ex, 12 tbl

FIELD: organic chemistry.

SUBSTANCE: claimed method includes catalytic dehydration of commercial 4,5,6,7-tetrahydroindole with 0.1-5.0 % nickel sulfide, carried on alumina, at 250-400°C in solvent in presence or absence of inert gas. Yield of target product is 92-96 % and selectivity is 100 %.

EFFECT: method of high yield and selectivity.

3 cl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 4,5,6,7-tetrahydroindole. Method involves interaction of cyclohexanone oxime with acetylene under about atmospheric pressure, in dimethylsulfoxide medium, in the presence of a complex of sodium cyclohexane oximate with dimethylsulfoxide (DMSO) in the ratio 1:1 of the formula: as a catalyst. Catalyst is prepared by interaction of cyclohexanone oxime with sodium hydroxide in DMSO medium followed by azeotropic distillation of water formed wherein benzene, cyclohexane or toluene and, preferably, toluene is used as an azeotropic agent, and process is carried out at temperature 100-140°C. The end substance is isolated by distillation of the reaction mixture after its neutralization and dimethylsulfoxide and the crude end substance are separated followed by extraction of the crude substance in a two-phase system consisting of alkaline metal hydroxide aqueous solution and toluene as a hydrocarbon solvent. Method provides preparing the end product with the yield 94-97% and purity 99.1-99.3%.

EFFECT: improved method of synthesis.

8 cl, 6 sch, 11 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of novel intermediate indoline compounds of the general formula (VIII): wherein R1 means (C1-C20)-alkylcarbonyl; R2 and R3 are similar or different and each means a lower alkyl group; R4 means hydrogen atom (H), (C1-C4)-alkyl or its salts. Method involves addition of pivaloyl group to compound of the general formula (VII): wherein R1, R2, R3 and R4 are given above, or its salt.

EFFECT: improved method of synthesis.

2 cl, 24 ex

FIELD: organic chemistry, medicine, pharmaceutical chemistry.

SUBSTANCE: invention relates to new compound - 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole mesylate and its hydrates. Indicated mesylate salt exceeds other 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole salts by its antiviral activity and can be used in different medicinal formulations. Invention expands assortment of agents used for treatment of viral infection. New antiviral agent shows high effectiveness treatment and low toxicity.

EFFECT: enhanced and valuable medicinal properties of agent and composition.

3 cl, 6 tbl, 9 ex

The invention relates to new 2-R-7a-methyl-3-(spirocyclohexane-2,5-Dien-4-one)-targetonline-1 of the formula I

< / BR>
where R - SCH3;6H5; CH2COOC2H5,

which show anti-inflammatory and analgesic activity, are relatively harmless compounds and can be used in the pharmaceutical industry

FIELD: medicine, veterinary science.

SUBSTANCE: invention concerns veterinary medicine. vaccine contains inactivated antigen and adjuvant. The antigen contained in the vaccine is cell suspension of germ Pseudomonas aeruginosa pure culture. The culture is obtained by selecting target affected organs of fallen nutrias are taken from a local epizootic nidus, preparing suspension, inoculating in differentially diagnostic media, evolving pure culture of the germ and growing the culture in meat infusion broth until microbe cell concentration of 5-6 milliard per 1 cm3 is achieved. The vaccine also contains formalin and aluminium hydroxide in the following wt % ratio: cell suspension of germ Pseudomonas aeruginosa pure culture evolved from target affected organs of fallen nutria from a local epizootic nidus in meat infusion broth with titre of 5-6 milliard of microbal cells per 1 cm3- 83.0-85.5, formalin - 1.0-2.0, the remainder being aluminium hydroxide.

EFFECT: vaccine is safe, highly immunogenic and stable during storage.

1 tbl, 5 ex

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