Substituted [1.3]oxazolo[4,5-d]pyridazine and combinatorial library

 

The invention relates to new physiologically active substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3) and combinatorial library designed to search among them physiologically active substances, compounds leaders and candidates (drug-candidates) on the basis of screening. When tested compounds showed the ability to inhibit the activity of protein kinases. In compounds

R1and R2each independently from each other represent a hydrogen atom, an inert Deputy selected from the group comprising optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted alkaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonyl, -(CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C13and R4each independently from each other represent: a hydrogen atom, -CN, -Cl, -Br, -I, carboxyl group, optionally substituted carboxy - C1-6alkyl group, optionally substituted karbamoilnuyu group, optionally substituted hydroxyl group, optionally substituted hydraxis1-5alkyl, optionally substituted amino1-7alkyl, optionally substituted by an amino group, azaheterocycle-N-yl, or substituted azaheterocycle-N-yl, inert Deputy selected from the group comprising optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted alkaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonyl, -(CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)nwhere n and m have a value from 1 to 7, optionally substituted aryloxyalkyl, optionally substituted whom This invention relates to the search for new chemical substances and new physiologically active substances, compounds leaders and candidates (drug-candidates) can be derived from the screening of combinatorial libraries.

More specifically, the present invention relates to new oxazolo [4,5-d]pyridazine and combinatorial library of this series of compounds.

Background of invention

Azolopyrimidine are highly physiologically active potential. So, for example, substituted 1,2,4-triazolo[2,3-b]pyridazine have anti-inflammatory, Antiasthmatic [Miyake, A.; Kawano, Y.; Ashida, A. (Takeda Chemical Industries, Ltd.), EP 0562439; JP 1994279447; US 5389633; US 5482939. J. Lewis, P. J. Shea, (Aventis Pharmaceuticals, Inc.), US 4136182], hypotensive [G. R. Jr.Allen, J. W. Jr.Hanifin, D. B. Moran, J. D. Albright. US 4112095] and anxiolytic effect [J. L. Castro Pineiro, L. J. Street, M. G. Russell, K. W. Moore, A. R. Guiblin, W. R. Carling, H. B. Broughton, A. Madin (Merck Sharp & Dohme Ltd.), WO 9804559; EP 0915875], and the substituted pyrazolo[3,4-d]pyridazine, thiazolo[4,5-d]pyridazine and triazolo[4,5-d]pyridazine imidazo[4,5-d]pyridazine possess anticancer activity [A. Tetsuya, M. Shogo, I. Fumio, Y. Masuo, N. Masafumi (Takeda Chemical Industries, Ltd.), EP 0733633].

Given the high physiologically active potential azolopyrimidine relevant is the development of new classes of this type of heterocyclic compounds and combinatorial libraries comprising these compounds to search for biologically active leaders.

There were only few representatives of this series of compounds, in particular, is known for substituted 2-(2,2-dimethyl-[1,3]dioxolane-4-yl)-4-hydroxy-6N-oxazolo[4,5-d]pyridazin-7-he [M. Yokoyama, M. Irie, K. Sujino, T. Kagemoto, H. Togo, M. Funabashi. J. Chem. Soc. Perkin Tr. 1, 1992, 2127-2134], whose synthesis is carried out in connection with the proof of the structure of the corresponding dimethyl [1,3]oxazol-4,5-in primary forms according to the following scheme

Also known 7-chloro-2-phenyloxazolo[4,5-d]pyridazin [Ruraishi, N. Chem. & Pharm. Bull. (Tokyo), 1958, 6, 641-644], 2-amino-7-chlorzoxazone[4,5-d]pyridazin, N'-(7-chlorzoxazone[4,5-d]pyridazin-2-yl)-N,N-dimethylformamide, N-hydroxy-N'-(7-chlorzoxazone[4,5-d]pyridazin-2-yl)-formamidine and N-amino-N'-(7-chlorzoxazone[4,5-d]pyridazin-2-yl)-formamidine [Marslavic, M.; Stanovnik. Century; Tišler, M. Monatshefte fuer Chemie, 1985, 116 (12), 1447-1458], oxazolo[4,5-d]pyridazin-2-yl-acetanilide [Harnisch, H. U.S. Pat. USA, 3985763, 1976] and poly 2,6-(oxazolo[4,5-d]pyridazin [Kurkov, V. P. Pat. USA, 4505840, 1985].

Information about biological activity oxazolo[4,5-d]pyridazines in the scientific and patent literature up to the present time absent.

Detailed description izobreteniya library” means a group of compounds, obtained by parallel synthesis, designed to search for connections-hit or leader, as well as to optimize the physiological activity of hit or leader, each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

“Focused library” means a combinatorial library, or a combination of several combinatorial library, or a set of libraries and substances, specially organized for the purpose of increasing the probability of finding hits and leaders, or to improve the efficiency of their optimization. The design of focused libraries, typically associated with directional search effectors (inhibitors, activators, agonists, antagonists, etc.) certain biological targets (enzymes, receptors, ion channels, etc).

“NH-Protective Deputy” means a chemical moiety that is attached to scaffold or semi-synthesis for the temporary protection of amino groups in multifunctional compounds.

“Nucleophilic Deputy” means a chemical moiety that is attached to scaffold in the reaction with nucleophilic reagents, for example, selected from the group p is the mean chemical radical, which joins scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic halides, organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothioscyanates.

“Aryl” means one or more aromatic cycles, each of which includes 5 or 6 carbon atoms. “Aryl” may be condensed political, such as naphthalene or unfused, such as biphenyl. “Substituted aryl” has one or more “not interfering” deputies.

“Halogen” means fluorine atom, chlorine, bromine or iodine.

“Heterocycle” means one or more saturated, unsaturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. “Heterocycle” may be condensed political, such as benzimidazole, benzoxazole, benzthiazole, quinoline or unfused, for example, as bipyridyl. “Azaheterocycle” means a heterocycle, including the azole, the quinoline.

“NH-Protective Deputy” means a chemical moiety that is attached to scaffold or semi-synthesis for the temporary protection of amino groups in multifunctional compounds including, but not limited to: amide Deputy, such as formyl, optionally substituted acetyl (for example, trichloroacetyl, TRIFLUOROACETYL 3-phenylpropionyl and others), optionally substituted benzoyl and others; urethane Deputy, such as optionally substituted C1-C7allyloxycarbonyl, for example, methyloxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and others; optionally substituted C1-C7alkyl substituent, for example, tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylfluorene and others; sulfanilic Deputy, for example, benzazolyl, p-toluensulfonyl etc.

“Nucleophilic Deputy” means a chemical moiety that is attached to scaffold in the reaction with nucleophilic reagents, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

“Electrophilic Deputy” means a chemical moiety that is attached to scaffold in Mesenich C1-C7alkylhalogenide, optionally substituted aryls1-C7alkylhalogenide, optionally substituted heterocyclyl1-C7alkylhalogenide, optionally substituted aryl halides, optionally substituted heterocyclisation), organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothioscyanates.

“Aryl” means one or more aromatic cycles, each of which includes 5 or 6 carbon atoms. “Aryl” may be condensed political, such as naphthalene or unfused, such as biphenyl. “Substituted aryl” has one or more “not interfering” deputies.

“Halogen” means fluorine atom, chlorine, bromine or iodine.

“Heterocycle” means one or more saturated, unsaturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen.

“Heterocycle” may be condensed politicla, for example, as will benzimidazolium a heterocycle, including at least one nitrogen atom, such as piperidine, morpholine, pyrrole, benzimidazole, benzoxazole, benzthiazole, quinoline.

“Substituted heterocycle” means a heterocycle having one or more “not interfering” deputies.

“Substituted azaheterocycle” means azaheterocycle having one or more “not interfering” deputies.

“Parallel synthesis” means a method for chemical synthesis of combinatorial libraries of individual compounds.

The aim of the present invention is a new [1,3]oxazolo[4,5-d]pyridazine General formula (1), (2) or (3):

in which R1and R2each independently of one another, represent: a hydrogen atom, an inert Deputy, or electrophilic Deputy selected from the group of organic halides, such as optionally substituted C1-C7alkylhalogenide, optionally substituted aryls1-C7alkylhalogenide, optionally substituted heterocyclyl C1-C7alkylhalogenide, optionally substituted aryl halides, optionally substituted heterocyclyl halides;

R1-6alkyl group, optionally substituted karbamoilnuyu group, optionally substituted hydroxyl group, optionally substituted hydraxis1-5alkyl, optionally substituted amino1-7alkyl, optionally substituted by an amino group, azaheterocycle-N-yl, or substituted azaheterocycle-N-yl;

excluding 7-chloro-2-phenyloxazolo[4,5-d]pyridazine, 2-amino-7-chlorzoxazone[4,5-d]pyridazin, N'-(7-chlorzoxazone[4,5-d]pyridazin-2-yl)-N,N-dimethylformamide, N-hydroxy-N'-(7-chlorzoxazone[4,5-d]pyridazin-2-yl)-formamidine, N-amino-N'-(7-chlorzoxazone[4,5-d]pyridazin-2-yl)-formamidine, oxazolo[4,5-d]pyridazin-2-yl-acetanilide, and poly 2,6-(oxazolo[4,5-d]pyridazin.

The aim of the present invention is also a new combinatorial library oxazolo[4,5-d]pyridazines of General formula (1), (2) and (3).

Preferred variants of the embodiment of the invention

The preferred option of the invention are new [1,3]oxazolo[4,5-d]-pyridazine General formula (1), (2) or (3) and a combinatorial library of new [1,3]oxazolo-[4,5-d]pyridazines of General formula (1), (2) or (3).

Particularly preferred new compounds are:

[1,3]oxazolo[4,5-d]pyridazin-2(3H),7(6H)-dione of the formula (1.1):

in which R1= has the above meaning;

3-substituted [1,3]oxazolo[4,5-d]pyridazin-2(3H),7(6H)-diones of General formula (1.3)

in which R2= has the above meaning;

3,6-disubstituted [1,3]oxazolo[4,5-d]pyridazin-2(3H),7(6H)-diones of General formula (1.4)

in which R1and R2= have the above meaning;

2-substituted [1,3]oxazolo[4,5-d]pyridazin-7(6H)-ones of General formula (2.1):

in which R3have the above meaning;

2,6-disubstituted [1,3]oxazolo[4,5-d]pyridazin-7(6H)-ones of General formula (2.2):

in which R1and R3have the above meaning;

the preferred option of the invention is a combinatorial library [1,3]oxazolo[4,5-d]pyridazines of General formula (1), (2) or (3) which vary the substituents R1, R2, R3and R4with the above value.

Below the invention is described using specific examples of the preparation of specific compounds and combinatorial libraries. The structure of the obtained compounds was confirmed by chemical data, chromatographic was carried out using a special synths "CombiSyn-012-3000" [M Bar, A. Ivashchenko, patent of Russia 2180609, 2002; PCT WO 02/087740 A1, 2002] and equipment [Technology Platform. In Custom Chemistry; Chemical Diversity Labs, Inc.; San Diego, CA, 2002; p.5].

The following examples illustrate but do not limit the invention.

Examples.

General information. All solvents and reagents were obtained from commercial sources, such as ACROS (Belgium), Sigma-Aldrich (USA), Lancaster (England) and by Whom Divas (USA). The melting point (so square) were obtained on the instrument company Buchi (Switzerland) model-520.13The NMR spectra were obtained on a spectrometer of the company Bruker model AM-300 and model DRX-500 in dimethyl sulfoxide-d6chemical shifts are given in the scale(ppm). The internal standard tetramethylsilane was. Mass spectra were measured on a device Kratos Model MS-890.

Analytical TLC was performed on silica gel on aluminium plates Silufol UV254(5 cm15 cm) (Kavalier, Czech Republic) or on glass plates with 0.25 mm layer of silica gel 60 F254(Merck, Germany). Visualization was accomplished with UV light at a wavelength of 254 nm. For chromatographic purification of used silica gel 5-40m (Chemapol, Czech Republic). In accordance with these LC/MS all the synthesized compounds had contents ALOR-3(2H)-pyridazinone 6 {1} in 40 ml of dimethylformamide was added a solution of 12 g (170 mmole) of sodium nitrite in 15 ml of water. The mixture was heated 5 h before the termination of allocation of oxides of nitrogen, was cooled, the precipitated crystals were filtered, mixed with 50 ml of warm 6 N hydrochloric acid, then cooled and filtered yellow crystals. Received 5 g (65%) 4-hydroxy-5-nitro-3(2H)-pyridazinone 6 {1} : N1NMR,: 1.068 (t, 6H), 3.246 (q, 4H), 8.1 (d, J=4.4 Hz, 1H), 8.1 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 8.3 (d, J=8.8 Hz, 1H), 9.2 (d, J=4.4 Hz, 1H), 9.3 (d, J=2.1 Hz, 1H), 14.17 (bs, 1H). Was first made 15 g of nitro-derivatives 6 {1} in a mixture of 100 ml ethanol and 50 ml water in the presence of 150 mg of platinum oxide for 2 at hydrogen and at 50C. the Warm solution was filtered and cooled. The precipitated product was filtered and recrystallized from water. Received 6 g (50%) of 5-amino-4-hydroxy-3(2H)-pyridazinone 7 {1} : LC-MS m/z 128 (M+1). The mixture was heated 904 mg of the obtained product 7 {1} and 770 mg of 1,1'-carbonyldiimidazole in 6 ml of dioxane for 1000 seconds at 170C in a microwave reactor. The reaction mass was cooled, the precipitate was filtered and recrystallized mixture of dioxane:water (9:1). Received 260 mg (42%) of the target product 1.1:LC-MS m/z 154 (M+1).

Example 2. 6-Phenyl[1,3]oxazolo[4,5-d]pyridazin-2(3H),7(6H)-dione 1.1 {2}. The original 4-hydroxy-5-nitro-2-phenyl-3(2H)-pyridazinone 6 {2} was obtained with the yield 67%, by analogy with 4-hydroxy-5-nitro-3(keilformige was added 50% aqueous suspension of 200 mg of 10% Pd on coal and 5.0 equivalents of cyclohexene, formate ammonium or formate of teatimony. The reaction mixture is boiled under stirring for 15-30 minutes (in the case of dimethylformamide, was kept 24 h at room temperature). The reaction mixture was filtered, the solvent is kept in vacuum, the residue was washed with water and recrystallized from ethanol. Received 5-amino-4-hydroxy-2-phenyl-3(2H)-pyridazinone 7 {2} with a quantitative yield.1H-NMR (DMSO-d6) 5.63 (brs, 2H), 7.35 (t, J=7.3 Hz, 1H), 7.45 (t, J=7.3 Hz, 2H), 7.54 (d, J=7.3 Hz, 2H), 7.71 (s, 1H), 9.40 (brs, 1H);13C-NMR (DMSO-d6) 125.8, 127.5, 128.7, 131.9, 132.2, 133.6, 142.3, 157.0; LC MS m/z 204.1 (M+1). Was dissolved 3.0 g (of 14.8 mmol) obtained 7 {2} in 30 ml of dioxane was added to the obtained solution of 2.9 g (1.2 equivalents) of 1,1'-carbonyldiimidazole. The mixture is boiled under stirring for 30 minutes the Solvent is kept in vacuum, and the residue was dissolved in 30 ml of water was added 40 ml of 1.0 M hydrochloric acid. The resulting suspension was cooled and filtered. The filter cake was washed with water and dried in the air. Got to 3.16 g (93%) of the desired product 1.1 {2} in the form of slightly yellow crystals,1H-NMR (DMSO-d6) 7.4-7.5 (m, 5H), 8.33 (s, 1H);13C-NMR (DMSO-d6) 126.3, 126.4, 128.7, 129.1, 131.8, 135.5, 141.5, 150.8, 153.8; LC MS m/z 230.0 (M+1).

Example 3. 3-Benzyl[1,3]oxazolo[4,5-d]pyridazin-2(3H),7(6H)-dione 1.2 {1}. To a mixture of 1 mmole [1,3]oxazolo[4,5-d]Piri is 5 ml of dioxane. After completion of the reaction (monitoring by LC MS), the reaction mixture was diluted with water and the product was extracted with dichloromethane. The solvent is kept off, and the product was purified using flash chromatography on silica gel using a mixture of dichloromethane and tetrahydrofuran as additionally separated by. Received the product 1.2 {1} with the release of 54%. SN-NMR 5.04 (s, 1H), 7.28-7.44 (m, 5H), 8.31 (s, 1H), 13.46 (bs, 1H); MS m/z 244 (M+1).

Example 4. A combinatorial library of 2-substituted [1,3]oxazolo[4,5-d]pyridazin-7(6H)-ones 2.1 {1-4}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer downloaded a mixture of 254 mg (2 mmol) of 5-amino-4-hydroxy-3(2H)-pyridazinone 7 {1} , 3 mmol of the appropriate acid or nitrile, and 0.5 ml of 15% solution of phosphoric acid in N-organic mixed at 230With over 800-1000 seconds in a microwave reactor. The reaction mass was dissolved in minimum amount of DMSO, and then diluted with water and was extracted with dichloroethane. The organic layer was washed with water, sodium bicarbonate solution, again with water and evaporated in vacuum. The residue was analyzed by the method LC MS. If necessary the 2.1 product was purified flash chromatography on silica gel with a mixture of dichloromethane and Tetra is R: 1.02-1.21 (m, 4H), 1.36-1.54 (m, 4H), 1.94-2.04 (m, 2H), 2.20 (bs, 1H), 2.77-2.99 (m, 2H), 8.51 (s, 1H), 13.35 (bs, 1H). MS m/z 246 (M+1).

Example 6. 2-(2-Naphthyl)[1,3]oxazolo[4,5-d]pyridazin-7(6H)-2.1 {2} : yield 81%.1H-NMR: 7.60-7.70 (m, 2H), 7.98-8.22 (m, 4H), 8.61 (s, 1H), 8.81 (s, 1H), 13.43 (bs, 1H). MS m/z 263 (M+1).

Example 7. 2-(2-Terbisil)[1,3]oxazolo[4,5-d]pyridazin-7(6H)-2.1 {3} : yield 63%.1H-NMR: 4.49 (s, 2H), 7.02-7.11 (m, 1H), 7.21-7.30 (m, 2H), 7.35-7.45 (m, 1H); 8.51 (s, 1H). MS m/z 245 (M+1).

Example 8. 2-(2-Forfinal)[1,3]oxazolo[4,5-d]pyridazin-7(6H)-2.1 {4} : yield 77%.1H-NMR: 7.45-7.58 (m, 2H), 7.72-7.81 (m, 1H), 8.22 (t, J=7.5 Hz, 1H), 13.47 (bs, 1H). MS m/z 231 (M+1).

Examples 9, 10. A common way to obtain a 6-substituted 2-(bicyclo [2.2.1] hept-2-yl-methyl) [1,3]-oxazolo [4,5-d] pyridazin-7(6H)-ones 2.2 {1, 2}. Was obtained by alkylation of 2-(bicyclo[2.2.1]hept-2-yl)[1,3]oxazolo[4,5-d]pyridazin-7(6H)-it 1.2 {1} , respectively benzyl bromide or etymologization, in conditions similar to those described in example 3.

Example 11. 6-Benzyl 2-(bicyclo[2.2.1]hept-2-yl-methyl)[1,3]oxazolo-[4,5-d]pyridazin-7(6H)-2.2 {1} : yield 45%.1H-NMR: 1.05-1.27 (m, 4H), 1.40-1.52 (m, 4H), 1.94-2.10 (m, 2H), 2.20 (bs, 1H), 2.78-3.03 (m, 2H), 5.39 (s, 2H), 7.20-7.40 (m, 5H), 8.60 (s, 1H). MS m/z 336(M+1).

Example 12. Ethyl {2-(bicyclo[2.2.1]hept-2-yl-methyl)-7-oxo[1,3]-oxazolo[4,5-d]pyridazin-7(6H)-yl} acetate 2.2 {2} : yield 48%.1H-NMR: 1.05-1.23 (m, 7H), 1.38-1.50 (m, 4H), 1.95-2.08 (m, 2H), 2.22 (bs, 1H), 2.78-3.06 (m, 2H), 4.15 (q, J=7.9 Hz), 5.01 (s, 2H), 8.61 (s, 1H). MS m/z 332 (M+1).

Primeridian 7 {2} , 4 mmole (416 mg), 2-cyanopyridine and 0.5 ml of 15% polyphosphoric acid was dissolved in N-organic under stirring and heated in a microwave reactor at 180With over 500 seconds. After cooling the reaction mass was dissolved in dimethylformamide, was diluted with water and was extracted with dichloromethane. The extract was washed with water, sodium carbonate solution, again with water, dried with anhydrous sodium sulfate, filtered and evaporated in vacuum. The residue was recrystallized from acetonitrile. Received 116 mg (40%) of the product 2.2 {3} with so pl. 251-254S.1H-NMR: 8.86 (m, 2H), 8.40-8.37 (d,1H), 8.13 (t, 1H), 7.75-7.71 (dd, 1H), 7.62-7.48 (m, 5H); LC-MS m/z 291.1 [M+1].

Example 14. Ethyl 2-{3-benzyl-2,7-dioxo-3,7-dihydro[1,3]oxazolo[4,5-d]pyridazin-6(2H)-yl}acetate 3.1 {1}. Was obtained by alkylation of 3-benzyl[1,3]-oxazolo[4,5-d]pyridazin-2(3H),7(6H)-dione 1.2 {1} etymologization in conditions similar to those described in example 3. Yield 62%.1H-NMR: 1.18 (t, J=7.5 Hz, 3H), 4.08 (q, 7.5 Hz, 2H), 4.95 (d, J=1.7 Hz, 2H), 5.05 (s, 1H); 7.30-7.45 (m, 5H), 8.37 (s, 1H). MS m/z 330 (M+1).

Example 15. 3,6-Dibenzyl[1,3]oxazolo[4,5-d]pyridazin-2(3H),7(6H)-dione 3.1 {2}. Was obtained by alkylation of 3-benzyl[1,3]oxazolo[4,5-d]pyridazin-2(3H),7(6H)-dione 1.2 {1} benzyl bromide in the same terms as provided in primaril)-2,7-dioxo-3,7-dihydro[1,3]oxazolo[4,5-d]pyridazin-6(2H)-yl}acetate 3.1 {1}. Was obtained by alkylation moll [1,3]oxazolo[4,5-d]pyridazin-2(3H),7(6H)-dione 1.1 etymologization in conditions similar to those described in example 3. Exit 34%,1H-NMR: 1.15-1.30 (m, 6H), 4.10-4.25 (m, 4H), 4.83 (s, 2H), 4.98 (s, 2H), 8.52 (s, 1H). MS m/z 326 (M+1).

Example 17. Focused library of new oxazolo[4,5-d]pyridazines of General formula (1). Of the synthesized oxazolo[4,5-d]pyridazines of General formula (1) selected 11 new oxazolo[4,5-d]pyridazines and was focused library, which was tested for the ability to inhibit the activity of protein kinases, which were determined as follows. The solution of the polypeptide (Calbiochem, USA), consisting of a random sequence of glutamic acid and tyrosine in the proportion 4:1, respectively, was maintained in the wells of 96-hole plates with optically transparent bottom during the night. During this time, the polypeptide firmly sorbirovtsa on the surface of the hole. Adsorbed polypeptide served as substrate for the kinase, which was fosfaurilirovania tyrosine in this polypeptide. Then 100 microliters 1U kinase (Calbiochem, USA, 1U is defined as the concentration of this enzyme is able to attach to the substrate 1 picomole phosphate for 1 minute) was added to the wells with the adsorbed polypeptide without testiruemi incubation, the solutions were removed by shaking from the wells and the wells were washed twice with saline. The wells were filled with 100 microlitres solution anti-phosphotyrosine monoclonal IGg antibodies conjugated with horseradish peroxidase from horseradish (Sigma, USA). The amount of bound peroxidase antibodies was determined by the activity of peroxidase, which in turn was determined by conversion speed peroxidase substrate (OPD, o-phenolenediamine dihydrochloride, Sigma) into a colored product. The concentration of the product formed in 30 minutes the reaction was determined by optical density at 490 nm, measured using a parallel 96-well reader VICTOR2V (Perkin Elmer, USA).

To calculate the percentage inhibition of kinase activity, each 96-well plate contained the following control wells: 1) the reaction solution containing all components except kinase; 2) the reaction solution together with the kinase. The optical density measured in control wells (1) was taken as zero activity (OD0), and the optical density measured in control wells (2) - 100% (OD100). The optical density measured in the presence of test compounds (ODi), was expressed as a percentage of the maximum activity and the percentage of inhibition of kinase activity was calculated by the following formula

The drawing shows the concentration dependence of inhibition of kinase activity of one of the detected active compounds (6) and one of the active compounds (1).

The table shows the magnitude of inhibition of ABL-kinase defined at a concentration corresponding compounds 30 microns.

Claims

1. Substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3)

in which R1and R2each independently from each other represent a hydrogen atom, an inert Deputy selected from the group comprising optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted aralkyl, optionally substituted is substituted on cycloalkenyl, optionally substituted aryl, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonyl, -(CH2)m-O-(C1-C7alkyl),-(CH2)m-N(C1-C7alkyl)nwhere n and m have a value from 1 to 7, optionally substituted aryloxyalkyl, optionally substituted heterocyclyl;

R3and R4each independently from each other represent: a hydrogen atom, -CN, -Cl, -Br, -I, carboxyl group, optionally substituted carboxy-C1-C6alkyl group, optionally substituted karbamoilnuyu group, optionally substituted hydroxyl group, optionally substituted hydraxis1-C5alkyl, optionally substituted amino1-C7alkyl, optionally substituted by an amino group, azaheterocycle-N-yl, or substituted azaheterocycle-N-yl, inert Deputy selected from the group comprising optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted alkaryl, optionally substituted cycloalkyl, nil, optionally substituted alkylsulfonyl, -(CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)nwhere n and m have a value from 1 to 7, optionally substituted aryloxyalkyl, optionally substituted heterocyclyl;

excluding 7-chloro-2-phenyloxazolo[4,5-d]pyridazine, 2-amino-7-chlorzoxazone[4,5-d]pyridazin, N'-(7-chlorzoxazone[4,5-d]pyridazin-2-yl)-N,N-dimethylformamide, N-hydroxy-N' -(7-chlorzoxazone [4,5-d] pyridazin-2-yl)-formamidine, N-amino-N'-(7-chlorzoxazone[4,5-d]pyridazin-2-yl)-formamidine, oxazolo[4,5-d]pyridazin-2-yl-acetanilide, and poly-2,6-(oxazolo[4,5-d]pyridazin).

2. Connection on p. 1 representing [1,3]oxazolo[4,5-d]pyridazin-(3H),7(6N)-dione (1.1) formula

3. Connection on p. 1, representing the 6-substituted [1,3]oxazolo[4,5-d]-

pyridazin-2(3H),7(6N)-diones of General formula (1.2)

in which R1have the above meaning.

4. Connection on p. 1, represents a 3-substituted [1,3]oxazolo[4,5-

d]-pyridazin-2(3H),7(6N)-diones of General formula (1.3)

in which R2have the above meaning.

5. Connection on p. 1 representing 3,6-disubstituted [1,3]oxazolo[4,5-

d]-pyridazin-2(3H),7 the data value.

6. Connection on p. 1 representing 2-substituted [1,3]oxazolo[4,5-d]-pyridazine-7(6N)-ones of General formula (2.1)

in which R3have the above meaning.

7. Connection on p. 1, represents a 2,6-disubstituted[1,3]oxazolo[4,5-d]-pyridazine-7(6N)-ones of General formula (2.2)

in which R1and R3have the above meaning.

8. Combinatorial library [1,3]oxazolo[4,5-d]pyridazines of General formula (1), (2) or (3) under item 1.

 

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