Method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(n,n-dimethylacetam ide), esters, crystalline esters, method for their preparing

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

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

 

The technical field

The invention relates to a new and improved method for producing 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide) formula:

and its pharmaceutically acceptable acid additive salts to new intermediate compounds used in the specified manner, and to a method for producing these intermediates.

The compound of Formula I is an excellent sedative agent, sold under the INN (International Nonproprietary Name) Zolpidem.

The level of technology

There are two ways of obtaining the compounds of Formula I.

According to the method described in the patent EP 50563, well-known compound 6-methyl-2-(4-were)imidazo[1,2-a]pyridine of the formula:

turn by the reaction of manniche 3-(N,N-dimethylaminomethyl)-6-methyl-2-(4-methyl-phenyl)imidazole[1,2-a]pyridine of the formula:

The last connection using iodotope bromide was transferred to the Quaternary salt thus obtained trimethylammonio derivative of the formula:

subjected to reaction with a cyanide of an alkali metal, the resultant combined acetonitrile derivative of formula:

subjected to acid hydrolysis, and then obrazovash is to be acetamide derivative of the formula:

subjected to alkaline hydrolysis. Thus obtained derivative of acetic acid of the formula:

by amidation converted into the desired compound of Formula I. the amidation Reaction can be done in two ways. According to one of the methods, the compound of Formula VIII is subjected to reaction with chloride tiomila and the resulting acid chloride of the acid of the formula:

subjected to reaction with dimethylamine. In the patent EP 50563 this method is not explained by examples. When performing this method, the authors of the present invention have found that the reaction product of the compounds of Formula VIII and chloride tiomila is a pitch black color that cannot be processed. Thus, the above method is not suitable for production on an industrial scale.

According to another method, a derivative of acetic acid of Formula VIII is subjected to reaction with carbonyl diimidazol in the presence of dimethylamine, whereby the desired compound of Formula I obtained through the connection of the Formula:

The disadvantage of this method is that carbonyldiimidazole is expensive, toxic, allergenic and hygroscopic compound, the manipulation of which is diversified in industrial production difficult. Another drawback is that the desired compound of Formula I is contaminated with decomposition products carbonyldiimidazole. Thus, Zolpidem, meet extremely stringent requirements of the Pharmacopoeia, can be obtained only with sophisticated cleaning methods.

The purpose of the patent EP 251589 is to eliminate the above disadvantages of the considered method. As a parent compound is 6-methyl-2-(4-were)imidazole[1,2-a]pyridine of formula III, which reacts with N,N-dimethyl-2,2-dimethoxyacetate formula

Derived α-hydroxy-N,N-dimethylacetamide formula:

subjected to reaction with chloride tiomila, after which derived from α-chloro-N,N-dimethylacetamide formula:

remove chlorine by reaction of recovery with sodium borohydride with the formation of the desired compounds of Formula I. the Disadvantage of this method is that N,N-dimethyl-2,2-dimethoxyacetate Formula XI is not available on an industrial scale and can only be obtained with the help of special equipment. In addition, the compound of Formula XI is sensitive to trace amounts of moisture and acids. The difficulty of obtaining compounds of Formula XI and the sensitivity to moisture and acids hinder the usage of this method on an industrial scale.

The invention

The purpose of the present invention is to eliminate the disadvantages of the known methods, and create a simple method of obtaining high purity of the drug Zolpidem, applicable on an industrial scale.

The above objective is achieved by the method of the present invention.

According to the aspect of the present invention is the method of obtaining 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide) of Formula I and its pharmaceutically acceptable acid additive salts, including interaction of the ester of General formula:

(where R is lower alkyl or phenyl-lower alkyl) dimethylamine in proton polar or aprotic solvent and, if necessary, the transformation of the thus obtained compounds of Formula I, its pharmaceutically acceptable acid additive salt.

According to another aspect of the present invention represented by the new esters of the General Formula II (where R is lower alkyl, with the exception of ethyl, or phenyl-lower alkyl and their pharmaceutically acceptable acid additive salt.

According to another aspect of the present invention represented by crystalline compounds of General Formula II and their pharmaceutically acceptable acid salt additive (where R is lower alkyl or phenyl-lower alkyl).

According to a further one is from the aspect of the present invention, is the method of producing esters of the General Formula II (where R is lower alkyl or phenyl-lower alkyl), comprising the esterification derivatives of acetic acid of Formula VIII.

Detailed description of the invention

The present invention is based on the recognition that the compound of the Formula I can be obtained in a pure form, without impurities, of the new compounds of General Formula II, not previously described, by using method, also feasible on an industrial scale.

The term "lower alkyl" refers to straight or branched alkyl groups containing 1-6 carbon atoms (e.g. methyl, ethyl,-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl or n-hexyl). The term "phenyl-lower alkyl" refers to lower alkyl groups as defined above, having as a substituent one or more phenyl groups (e.g. benzyl, β-phenylethyl, β,β-diphenylether etc).

According to the preferred implementation of the method of the invention, as the starting material are compounds of General Formula II in which R represents a methyl, ethyl, isopropyl or benzyl.

The reaction can be carried out in a polar proton or an aprotic solvent. As proton polar solvent is preferable to use lower alcohols (e.g., meta is ol, ethanol, n-propanol, isopropanol or n-butanol). As the aprotic solvent is preferable to use acetonitrile, dimethylformamide, dimethylsulfoxide or diamid hexamethylphosphoric acid. It is preferable to conduct the reaction in methanol, isopropanol or acetonitrile.

The reaction can be carried out with 5-50°C, preferably at room temperature.

It is preferable to saturate used as the reaction medium solvent reagent - dimethylamine, and to the thus obtained solution was added ether of the General Formula II.

The reaction mixture can be processed using very simple techniques. The desired compound of Formula I is precipitated from the solution in crystalline form and can be easily separated by filtration or by centrifugation.

According to a particularly preferred implementation of the method of the invention can proceed as follows:

After filtering, the compounds of Formula I, the mother liquor is saturated with gaseous dimethylamine, and thus unreacted compound of Formula II present in the mother liquor is converted into the desired compound of Formula I. Gaseous dimethylamine absorb at low temperature, preferably at a temperature of from -10 to +10°C. the Purity of the obtained while the second portion of the compounds of Formula I of Eden is ICNA the purity of the first portion of the product.

Thus obtained compound of the Formula I can be converted into pharmaceutically acceptable acid additive salt. For the formation of salts can be used pharmaceutically acceptable inorganic acid (e.g. hydrogen chloride, hydrogen bromide, nitric acid, phosphoric acid, sulfuric acid, etc. and organic acids (e.g. tartaric acid, succinic acid, maleic acid, fumaric acid, lactic acid, n-toluensulfonate etc). The formation of salts of conduct known per se manner, for example, by addition of a solution of the appropriate acid formed with an organic solvent, to a solution of the compounds of Formula I in an organic solvent. It is preferable to obtain a salt of tartaric acid the compounds of Formula I.

The method of the present invention has the following advantages:

- the method can be simply and preferably is made;

- does not require any expensive or special equipment;

- eliminated the use of raw materials and reagents that are difficult to handle and/or toxic;

the reaction products and uterine solutions are not harmful to the environment;

- no heat;

- the desired compound of Formula I can be isolated in pure form.

Most of the source from which dinani General Formula II are new. In the journal J. Med. Chem. 40, 3109 (1997) disclosed a General method of obtaining compounds of General Formula II, where R is ethyl. According to this method, 2-amino-5-methylpyridin subjected to cyclocondensation reaction with the corresponding bracketeers. Ethyl-[6-methyl-2-(4-methyl-phenyl)imidazole[1,2-a]pyridine-3-yl]acetate obtained as oil output 10%. Physico-chemical constants of compounds suitable for identification, not given. On the other hand, the compound of General Formula II, where R is ethyl, obtained according to the present invention is a crystalline substance (see Example 4).

In the method of the present invention, it is preferable to use the following compounds of General Formula II:

methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate;

ethyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate;

isopropyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate;

benzyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate.

Compounds of General Formula II can be obtained by known per se methods. According to the method, a derivative of acetic acid of Formula VIII etherification alcohol of General Formula:

(where R is as described above).

The reaction can be preferably carried out using an excess of the alcohol of General Formula XIV, in accordance with which he acts as agent, and ka is the solvent. The reaction is carried out in the presence of an acid catalyst, preferably hydrochloric acid, concentrated sulfuric acid or n-toluenesulfonic acid. The reaction can be conducted at temperatures from 20°C to the boiling point of the reaction mixture; preferably it is possible to operate at the boiling point. As the reaction medium can also be used not miscible with water, aromatic or chlorinated hydrocarbon (e.g. toluene or chloroform). In this case, the water formed during the reaction, is removed together with the solvent by azeotropic distillation. The reaction is carried out in the presence of an acid catalyst.

The compound of General Formula II is recovered from the reaction mixture by a known method. In some cases, the compound of General Formula II or its salt formed with the catalyst precipitates from the reaction mass. The solid is filtered off and the aqueous medium by using a bicarbonate or carbonate of an alkali metal is transferred into the base. The base, in most cases deposited from the solution in crystalline form, is filtered off, washed and, if necessary, recrystallized. The base, which remains in solution, extracted with an organic solvent not miscible with water, and separated from the extract by evaporation or crystallization. You can also make the identification of the distribution of the reaction mass between the solvent, not miscible with water, and ice water to remove the catalyst, separation of the layers, drying and evaporation of the organic phase and, finally, purification of the product by recrystallization or chromatography. If formed during the reaction water Argonauts azeotropic distillation, the reaction mass is decomposed with ice water, the layers separated and treated as described above.

The compound of General Formula II can also be obtained by transformation of a derivative of acetic acid of Formula VIII in the salt of an alkali metal and alkylation of the thus obtained salt of alkali metal halide of General Formula:

(where R is as defined above and X is halogen).

The salt formation can be carried out using alkali metal hydride (e.g. sodium hydride or potassium hydride), alkali metal amide (e.g. sodium amide or potassium amide or alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide). The preferred alkali metal hydroxide and work in aqueous, aqueous-alcoholic or alcoholic medium. Especially, it is preferable to dissolve a derivative of acetic acid of Formula VIII in an aqueous, aqueous-alcoholic or alcoholic solution of alkali metal hydroxide and to carry out the reaction of the thus obtained solution with a halide of Formula XV "in situ is, i.e. without isolating the salt of the alkali metal compounds of the Formula VIII. The reaction is carried out at a temperature of from -20°C to the boiling point of the solvent, preferably at the boiling point. Aqueous-alcoholic or alcoholic medium can be prepared with the use of alcohol, See (for example, methanol, ethanol, isopropanol, butanol and so on).

The reaction mass may be treated with conventional method. It is preferable to extract the reaction mass with an organic solvent (appropriate, halogenated hydrocarbon, for example dichloromethane or chloroform), followed by washing and evaporation of the extract.

A derivative of acetic acid of Formula VIII is a known compound and can be obtained as described in EP 50563.

Compounds of General Formula XIV and XV are commercially available products.

Additional details of the present invention should be sought in the following examples, the permissive character.

Example 1

Methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate

To a suspension of 28 g (0.1 mol) of [6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetic acid and 200 ml of methanol are added dropwise 6.9 ml (12.8 g, 0.13 mol) of concentrated sulfuric acid. The reaction mass is heated at boiling for 3 hours, after which by means of an external cooling is brought first to anatoy temperature, and then 5-10°C and stirred at this temperature for one hour. Precipitated crystalline product (sulfate salt of said compound) is filtered off, washed with methanol and dried. The resulting product is suspended in 500 ml of water, followed by addition of 10%aqueous sodium carbonate solution under vigorous stirring bring the pH up to 8. The precipitated product is filtered, washed twice with water portions 70 ml. Thus receive a 27.4 g of methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate as a crystalline substance of white color. The yield of 93.3%, so pl.: 133-136°C.

Elemental analysis: for the formula C18H18N2O2(294,36)

calculated: 73,45%, N 6,16%, N 9,52%

found: 73,58%, N 6,14%, N 9,62%

IR(KBR) 2950, 1729, 1538, 1503, 1437, 1408, 1391, 1332, 1308, 1273, 1229, 1177, 1133, 1042, 994, 890, 823, 787, 753, 737, 706, 587, 553, 514, 417.

PMR (CDCl3): δ, ppm 7.84 (1H, s, H-5), 7.69 (2H, d, J 8.0 Hz, H-2',6'), 7.56 (1H, d, J 9.2 Hz, H-8), 7.28 (2H, d, J 8.0 Hz, H-3',5'), 7.06 (1H, DD, J 1.5 and 9.2 Hz, H-7), 4.02 (2H, s, CH2), 3.76 (3H, s, CH3), 2.40 (3H, s, CH3-4'), 2.35 (3H, s, CH3-6).

NMR13With (CDCl3): δ, ppm, 169.9 (C=O), 144.3 (C-8A), 143.9 (C-2), 137.5 (C-4'), 131.2 (C-1'), 129.2 (C-3',5'), 128.2 (C-2',6'), 127.5 (C-7), 122.0 (C-5), 121.1 (C-6), 116.7 (C-8), 112.1 (C-3), 52.430.5 (CH2), 21.2 (CH3-4'), 18.3 (CH3-6).

Example 2

Methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-the l]acetate

Act as described in Example 1, except that sulfuric acid was replaced with 10 ml of 20%methanolic solution of hydrogen chloride and the reaction mass is heated at boiling for 8 hours. The methanol is removed, to the residue was added 200 ml of water, after which the pH is brought to 7 by adding 10%aqueous solution of sodium bicarbonate. The mixture is extracted three times with chloroform portions of 50 ml each.

The combined organic phases are washed with 50 ml of water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue is recrystallized from acetonitrile. So get to 21.0 g of methyl-[6-methyl-2-(4-were)-imidazol[1,2-a]pyridine-3-yl]acetate. Output to 71.5%. The product is in all respects identical with the compound obtained according to Example 1.

Example 3

Methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate

Act as described in Example 1, except that a methanol solution of hydrogen chloride replace 5.0 g of catalyst --toluenesulfonic acid and the reaction mass is heated at boiling for 6 hours. The crystalline product is recrystallized from acetonitrile. So get of 22.2 g of methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate, yield to 71.5%. The product is in all respects identical to the compound obtained in accordance With the ERU 1.

Example 4

Ethyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl)acetate

Act as described in Example 1, except that the methanol is replaced by ethanol. So get of 24.0 g of ethyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate, yield to 78.3%.

So pl.: 101-103°C.

Elemental analysis: for the formula C19H20N2O2(308,43)

calculated: 74,00%, N 6,54%, N remaining 9.08%

found: 74,17%, H 6.58 Percent, N 8,97%.

IR(KBR) 2983, 1725, 1537, 1503, 1391, 1367, 1345, 1326, 1307, 1272, 1225, 1185, 1143, 1058, 1021, 875, 824, 788, 737, 703, 584, 556, 515.

PMR (CDCl3): δ, ppm 7.88 (1H, s, H-5), 7.73 (2H, d, J 8.0 Hz, H-2',6'), 7.57 (1H, d, J 9.2 Hz, H-8), 7.28 (2H, d, J 8.0 Hz, H-3',5'), 7.07 (1H, DD, J 1.5 and 9.2 Hz, H-7), 4.00 (2H, s, CH2), 4.22 (2H, q, J 7.2 Hz,2.40 (3H, s, CH3-4'), 2.36 (3H, s, CH3-6), 1.28 (3H, t, J 7.2 Hz,

NMR13With (CDCl3): δ, ppm, 169.4 (C=O), 144.1 (C-8A), 143.8 (C-2), 137.5 (C-4'), 131.0 (C-1'), 129.3 (C-3',5'), 128.3 (C-2',6'), 127.6 (C-7), 122.0 (C-5), 121.3 (C-6), 116.6 (C-8), 112.3 (C-3), 61.530.8 (CH2), 21.2 (CH3-4'), 18.4 (CH3-6), 14.0

Example 5

Isopropyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate

Act as described in Example 1, except that the methanol is replaced by isopropanol. So get to 24.7 g of isopropyl-[6-methyl-2-(4-were)-imidazol[1,2-a]pyridine-3-yl]acetate, yield of 6.7%.

So pl.: 104-105,5°C.

Elemental analysis: for the formula C20H22N2O2(322,41)

calculated: 74,51%, N 6,88%, N 8,69%

found: 74,57%, N 6,92%, N 8,61%

IR (KBR) 2980, 1730, 1613, 1536, 1503, 1460, 1420, 1390, 1376, 1340, 1320, 1270, 1228, 1185, 1108, 1053, 973, 945, 901, 843, 817, 796, 757, 740, 726, 704, 625, 590, 559, 514.

PMR (CDCl3): δ, ppm 7.91 (1H, s, H-5), 7.74 (2H, d, J 8.0 Hz, H-2',6'), 7.57 (1H, d, J 9.0 Hz, H-8), 7.28 (2H, d, J 8.0 Hz, H-3',5'), 7.07 (1H, DD, 9.0 Hz, H-7), 5.08 (1H, d, J 6.2 Hz,3.97 (2H. with a, CH2), 2.40 (3H, s, CH3-4'), 2.36 (3H, s, CH3-6), 1.26 (6N, d, J 6.2 Hz,

NMR13With (CDCl3): δ, 169.0 ppm (C=O), 144.2 (C-8A), 143.8 (C-2), 137.5 (C-4'), 131.1 (C-1'), 129.2 (C-3',5'), 128.3 (C-2',6'), 127.5 (C-7), 121.9 (C-5), 121.3 (C-6), 116.6 (C-8), 112.5 (C-3), 69.231.1 (CH2), 21.721.2 (CH3-4'), 18.3 (CH3-6).

Example 6

Benzyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate

To a solution of 1 g (0,025 mol) of sodium hydroxide in 40 ml water is added 5.6 g (0.02 mol) of [6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetic acid, then added dropwise 2.5 ml (3.6 g, 0,021 mol) of benzyl bromide. The reaction mass is heated at the boil for one and a half hours, then cooled to room temperature and extracted twice with dichloromethane portions of 50 ml each. The organic phase is washed with 30 ml of 10%aqueous solution of caustic soda which I and 50 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated. The oily residue is triturated with petroleum ether. So get with 5.3 g of benzyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate, yield 71.0 per cent.

So pl.: 106-107°C.

Elemental analysis: for the formula C24H22N2O2(370,45)

calculated: 77,81%, N Of 5.99%, N 7,56%

found: 77,74%, N 6,03%, N to 7.59%

IR (KBR) 3032, 2920, 1719, 1538, 1501, 1450, 1409, 1378, 1346, 1319, 1304, 1266, 1247, 1180, 1141, 1122, 1050, 1020, 998, 970, 896, 825, 812, 740, 694, 581, 504.

PMR (CDCl3): δ, ppm 7.79 (1H, s, H-5), 7.69 (2H, d, J 8.0 Hz, H-2',6'), 7.55 (1H, d, J 9.1 Hz, H-8), ˜ 7.3 (5H, m, AGN), 7.22 (2H, d, J 7.8 Hz, H-3',5'), 7.04 (1H, DD, 9.1 Hz, H-7), 5.18 (2H, s, PhCH2), 4.04 (2H, s, CH2), 2.39 (3H, s, CH3-4'), 2.28 (3H, s, CH3-6).

NMR13With (CDCl3): δ, ppm, 169.3 (C=O), 144.3 (C-8A), 143.8 (C-2), 137.5 (C-4'), 131.0 (C-1'), 129.2 (C-3',5'), 128.3 (C-2',6'), 127.6 (C-7), 122.0 (C-5), 121.3 (C-6), 116.6 (C-8), 112.1 (C-3), 67.2 (PhCH2), 30.8 (CH2), 21.2 (CH3-4'), 18.3 (CH3-6).

Example 7

Methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate

To a suspension of 28 g (0.10 mol) of [6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetic acid, 200 ml of toluene and 10 ml of methanol is added dropwise with stirring was added 1.6 ml (2.9 g, 0.03 mol) of concentrated sulfuric acid. The reaction mass is refluxed for 4 hours with removal of water, cooled to room temperature, after cehapest 100 ml of water and 10%sodium hydrogen carbonate solution was adjusted pH to 7. The layers separated, and the aqueous phase is extracted with 50 ml of toluene. The combined organic fractions washed with 50 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is recrystallized from acetonitrile. So get 24,1 g of methyl-[6-methyl-2-(4-were)-imidazol[1,2-a]pyridine-3-yl]acetate. The product is in all respects identical with the compound obtained according to Example 1.

Example 8

Methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate

Act as described in Example 7, except that the concentrated sulfuric acid is replaced with 5 ml of concentrated hydrochloric acid and the reaction mass is refluxed for 5 hours. So get a 21.5 g of methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate. The product is in all respects identical with the compound obtained according to Example 1.

Example 9

6-Methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide)

of 30.7 g (of 0.68 mol) of gaseous dimethylamine absorb in 45 ml of anhydrous methanol at a temperature of from -5°0°With, then add 25 g (of 0.085 mol) of methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate. The reaction mass was stirred at room temperature for 7 days. Precipitated crystalline product is filtered off and paracrystalline is up from acetonitrile. So get 24,1 g of 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethyl-ndimethylacetamide). The yield of 92.2%. So pl.: 194-196°; purity determined by HPLC: 99.8 per cent.

Elemental analysis: for the formula C19H21H3(307, 40)

calculated: 74,24%, N 6,89%, N 13,67%

found: 73,78%, N 6,85%, N 13,73%

IR (KBR) 2916, 1637, 1539, 1505, 1424, 1395, 1345, 1265, 1219, 1189, 1139, 1062, 824, 795, 728, 605, 518.

PMR (CDCl3): δ, ppm 7.96 (1H, d, J 0.6 Hz, H-5), 7.55 (2H, d, J 8.0 Hz, H-2',6'), 7.52 (1H, d, J 9.2 Hz, H-8), 7.25 (2H, d, J 8.0 Hz, H-3',5'), 7.03 (1H, DD, J 1.5 and 9.2 Hz, H-7), 4.05 (2H, s, CH3), 2.93 (3H, s, N3), 2.87 (3H, s, N3), 2.39 (3H, s, CH3-4'), 2.32 (3H, s, CH3-6).

NMR13With (CDCl3): δ, ppm, 168.2 (C=O), 143.9 (C-8A), 143.5 (C-2), 137.4 (C-4'), 131.5 (C-1'), 129.3 (C-3',5'), 128.4 (C-2',6'), 127.6 (C-7), 122.2 (C-5), 121.8 (C-6), 116.4 (C-8), 113.6 (C-3), 37.4 (N3), 33.58 (N3), 30.2 (CH2), 21.2 (CH3-4'), 18.4 (CH3-6).

5.0 g (0.11 mol) of gaseous dimethylamine absorb in the mother liquor of the product obtained according to Example 9, at a temperature of from -5°0°C. the Reaction mass is stirred for 2 days. Thus receive an additional 1.7 g of the above compound, the yield of 6.5%. The purity of this product is identical to the purity of the base mass.

Example 10

6-Methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide)

Act as described in Example 9, except that the reaction of the spending is in a closed apparatus at 40° With in 2 days. Thus obtain 24.5 g of 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide), the output 93,8%. The product is in all respects identical with the compound obtained according to Example 9.

Example 11

6-Methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide)

Act as described in Example 9, except that the reaction mass is stirred at 5°within 10 days. The obtained crystalline material is recrystallized from acetonitrile. So get 16,1 g of 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide), the yield of 61.7%. The product is in all respects identical with the compound obtained according to Example 9.

Example 12

6-Methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide)

Act as described in Example 9, except that methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate to replace 26,2 g (of 0.085 mol) of ethyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate and methanol replace anhydrous ethanol. Thus obtain 20.7 g of 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide), the yield of 79.3 percent. The product is in all respects identical with the compound obtained according to Example 9.

Example 13

6-Methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide)

Act as described in Example 9,except what methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate to replace 26,6 g (of 0.085 mol) isopropyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate and methanol replace anhydrous isopropanol. The reaction mass is stirred for 48 hours at 50°C instead of room temperature. So get to 13.6 g of 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide), the yield of 51.2%. The product is in all respects identical with the compound obtained according to Example 9.

Example 14

6-Methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide)

Act as described in Example 9, except that methyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate to replace 31,5 g (of 0.085 mol) of benzyl-[6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-yl]acetate and methanol replace anhydrous acetonitrile. So get to 18.1 g of 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide), the yield of 69.5%. The product is in all respects identical with the compound obtained according to Example 9.

Example 15

6-Methyl-2-(4-were)imidazole[1.2-a]pyridine-3-(N,N-dimethylacetamide)-polytetra

10 g (0,033 mol) of 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide) was dissolved in 40 ml of anhydrous methanol, and then with stirring was added a solution of 2.44 g of L-(+)-tartaric acid in 10 ml of methanol. The reaction is ionic mass is stirred at room temperature for one hour. Precipitated crystalline substance was incubated over night in the refrigerator, filtered and washed with a small amount of ethanol. Thus obtain 11.3 g of 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethyl-ndimethylacetamide)polytetra in the form of a crystalline substance of white color. The yield of 92.7%. So pl.: 195-197°C.

The purity of the product by HPLC above 99.8%, and the total impurity content of less than 0.2%. The product fully meets the requirements of the European Pharmacopoeia Supplement 1998, 525.

Elemental analysis: for the formula C42H48N6About8(764,9)

calculated: 65,95%, N 6,33%, N 10,99%

found: 65,71%, N 6,23%, N 10,82%

IR (KBR) 3542, 3456, 2921, 1638, 1513, 1405, 1264, 1199, 1124, 1072, 918, 854, 797, 683, 599, 513.

PMR (CDCl3): δ, ppm 8.04 (1H, d, J 0.6 Hz, H-5), 7.52 (2H, d, J 8.0 Hz, H-2',6'), 7.51 (1H, d, J 9.2 Hz, H-8), 7.25 (2H, d, J 8.0 Hz, H-3',5'), 7.12 (1H, DD, J 1.6 and 9.2 Hz, H-7), 4.31 (1H, s), 4.12 (2H, s, CH2), 3.13 (3H, s, N3), 2.90 (3H, s, N3), 2.34 (3H, s, CH3-4'), 2.30 (3H, s, CH3-6).

NMR13With (CDCl3): δ, 173.4 ppm (COOH), 168.2 (C=O), 142.9 (C-8A), 142.5 (C-2), 136.7 (C-4'), 132.0 (C-1'), 129.3 (C-3',5'), 127.8 (C-2',6'), 127.3 (C-7), 122.6 (C-5), 120.9 (C-6), 115.9 (C-8), 115.4 (C-3), 72.3 (CH), 37.1 (N3), 35.5 (N3), 29.1 (CH2), 21.0 (CH3-4'), 18.0 (CH3-6).

1. The way to obtain 6-methyl-2-(4-were)imidazole[1,2-a]pyridine-3-(N,N-dimethylacetamide) formula

and it is farmacevtichesky acceptable acid additive salts, including the interaction of the ester of General formula

where R is lower alkyl or phenyl-lower alkyl, with dimethylamine in proton polar or aprotic solvent and, if necessary, the transformation of the thus obtained compounds of formula I, its pharmaceutically acceptable acid additive salt.

2. The method according to claim 1, comprising using as the starting material compounds of General formula II, where R is methyl, ethyl, isopropyl or benzyl.

3. The method according to claim 1, comprising carrying out the reaction at a temperature of 5-50°C.

4. The method according to claim 1, comprising conducting the reaction in methanol, ethanol, isopropanol or acetonitrile.

5. The method according to any one of claims 1 to 4, including the allocation of compounds of General formula I from the reaction mixture, the addition of dimethylamine to the stock solution and the extract thus obtained compounds of General formula I from the mother liquor.

6. Esters of General formula II

where R is lower alkyl, with the exception of ethyl, or phenyl-lower alkyl.

7. Esters of General formula II according to claim 6, where R is methyl, isopropyl or benzyl.

8. Crystalline esters of the General formula II

where R is lower alkyl or phenyl - lower alkyl.

9. Crystal E. the Ira General formula II according to claim 8, where R is methyl, ethyl, isopropyl or benzyl.

10. The method of producing esters of the General formula II

where R is lower alkyl or phenyl-lower alkyl, characterized in that atrificial derivative of acetic acid of formula VIII

11. The method according to claim 10, characterized in that the compound of formula VIII etherification alcohol of General formula

where R has the same meaning specified in paragraph 10.

12. The method according to claim 11, characterized in that the reaction is carried out in the presence of an acid catalyst.

13. The method according to item 12, characterized in that as the acid catalyst using hydrogen chloride, concentrated sulfuric acid or p-toluensulfonate.

14. The method according to claim 10, characterized in that the acid of formula VIII is converted into the salt of alkali metal alkylate specified salt halide of General formula

where R is as indicated in paragraph 10, and X is halogen.

15. The method according to 14, characterized in that the salt of an alkali metal is produced by interaction with alkali metal hydroxide in an aqueous, aqueous-alcoholic or alcoholic solution.

16. The method according to 14 or 15, characterized in that use soedineniya formula XV, where X is chlorine or bromine.



 

Same patents:

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

The invention relates to crystalline polyhydroxylated 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of formula (VI)

The invention relates to a method for the synthesis of nitrogen-containing heterocyclic compounds, in particular the production of substituted pyrido[1,2-][1,3] benzimidazole of General formula

where 1 R=NO2, R1=H;

2 R=CF3, R1=H;

3 R=CN, R1=H;

4 R=R1=CN

The invention relates to heterocyclic compounds with substituted phenyl group of formula Ior its pharmaceutically acceptable salt, in which R1represents a C1-C6alkyl; R2represents a C1-C6alkyl; R3represents H or halogen andrepresents a substituted heterocycle, as defined in paragraph 1 of the claims; and X represents NH or O

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

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

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

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