The method of obtaining substituted pyrido[1,2-a][1,3]benzimidazole

 

(57) Abstract:

Describes how to obtain the substituted pyrido[1,2-a]-[1,3]benzimidazole of General formula

where 1 R=NO2, Rl=H;

2 R=CF3, Rl=H;

3 R=CN, Rl=H;

4 R=R1=CN,

which can be used as intermediates in the synthesis of fluorescent and biologically active substances. The method consists in the reaction of 2-nitro-4-R-5-P1-halogenase with pyridine and the recovery of the salts of N-(2-nitro-4-R-5-R1-phenyl)pyridinium, and the interaction of 2-nitro-4-R-5-R1-halogenation with pyridine is carried out at a temperature of 20°C and a molar ratio of 2-nitro-4-R-5-Rl-halogenase:pyridine=l:7, and the restoration is subjected to alcoholic salt solution with a solution of SnCl22H2O 3% model HC1 at a molar ratio of the salt of N-(2-nitro-4-R-5-R1-phenyl)-pyridinium: SnCl22H2O=1:3 at a temperature of 20°C for 0,12 including the Described method allows to obtain the target product with high yield and purity of the available raw materials at room temperature and in a short period of time. table 2.

The invention relates to a method for the synthesis of nitrogen-containing heterocyclic compounds, in particular the production of substituted n, 1=N;

3 R=CN, R1=H;

4 R=R1=CN.

which can be used as intermediates in the synthesis of fluorescent and biologically active substances. The claimed compounds are:

7 nitropyrene[1,2-a][1,3]benzimidazole (1):

7-(trifluoromethyl)pyrido[1,2-a][1,3]benzimidazole (2):

pyrido [1,2-a][1,3] benzimidazole-7-carbonitrile (3):

pyrido[1,2-a][1,3]benzimidazole-7,8-dicarbonitrile (4):

A method of obtaining substituted pyrido[1,2-a][1,3]benzimidazole based on the interaction of pekelharing or 2,4-dinitrochlorobenzene with 2-aminopyridine in benzene at 20°C and cyclization of the obtained compounds boiling at a temperature of 190°C in N,N-dimethylaniline 2.5 hours in a nitrogen atmosphere (Morgan S. G., Stewart J. // J. Chem. Soc., 1938, No. 8, p.1057).

where R=H, NO2

The disadvantages of this method of synthesis of substituted pyrido[1,2-a][1,3]-benzimidazole are: the use of expensive 2-aminopyridine as a source of reagent, as well as the relatively harsh conditions, which is unacceptable for components of nucleic acids.

The purpose of the invention is reducing the cost of synthesis, reducing the time and the is achieved by as source reagent instead of 2-aminopyridine is used cheaper pyridine, the interaction of pyridine with 2-nitro-4-R-5-K1-halogenation carried out at a temperature of 20°C and a molar ratio of 2-nitro-4-R-5-R1-halogenase:pyridine =1:7, within 1 hour, recovering alcoholic solution of salt of N-(2-nitro-4-R-5-R1-phenyl)pyridinium carried out with a solution of SnCl22H2O in 3% hydrochloric acid and a molar ratio salt of N-(2-nitro-4-R-5-R1-phenyl)pyridinium: Snl22H2O=1:3 at a temperature of 20°C for 0,12 h, which allows to reduce the temperature of the cyclization reaction with 190°C to 2.0C and to reduce the process time from 2.5 hours to 0.12 h

where X=Cl, Br

1 R=NO2, R1=H;

2 R=CF3, Rl=H;

3 R=CN, Rl=H;

4 R=Rl=CN.

The structure and purity of intermediates and target pyrido[1,2-a]-[1,3]benzimidazole were analyzed by the method of the PMR, the melting point and elemental composition.

The invention is illustrated by the following examples.

Example 1. N-(2-nitro-4-triptoreline)pyridine chloride 5 g (0,022 mol) of 2-nitro-4-cryptomaterial contribute 11.7 ml (0,154 mol) of pyridine and stirred at a temperature of 20C for 1 hour. Dropped the Nile)pyridinium chloride - white powder, So pl. 260-262°C.

Found, %: From 46.9; H 2,6; N 9,3

Calculated, %: C 47,3; H 2,6; N 9,2

1N PMR (DMSO-d6) , MD: to 9.57 (d, 2H, J=8,1), 8,98 (t, 1H, J=15,2), 8,67 (s,1H), and 8.6 (d, 1H, J=8,0), 8,48 (d, 1H, J=8,2), 8,42 (t, 2H, J=13.3-Inch)

Examples 2-4. Salt N-(2-NO2-4-R-5-R1-phenyl)pyridinium get analogously to example 1. Physico-chemical characterization of salts of N-(2-NO2-4-R-5-R1-phenyl)pyridinium shown in table 1.

Example 5. 7-(Trifluoromethyl)pyrido[1,2-a][1,3]benzimidazole

To 5 g (0,016) salt of N-(2-NO2-4-triptoreline)pyridinium in 20 ml of ethanol is introduced under stirring 11,13 g (0,048 mol) SnCl22H2O in 20 ml of 3% hydrochloric acid. Through 0,12 h, the reaction mixture podslushivaet 25% aqueous ammonia solution to pH=7-8 and extracted with several portions of chloroform (=200 ml). After distillation of the chloroform obtain 3.7 g (98% of theory) of 7-(trifluoromethyl)pyrido[1,2-a][1,3]benzimidazole - white powder, So pl. 233-235°C.

Found, %: C 60,7; N 3,3; N 12,0

Calculated, %: C 61,0; H 3,0; N 11,9

1N PMR (DMSO-d6), MD: 9,16 (d, 1H, J=7,80), 8,53 (d, 1H, J-8,0), of 8.15 (s, 1H), 7,74 (d, 1H, J=7,9), 7,66 (m, 2H), to 7.09 (t, 1H, J=14,8)

Examples 6-7. Substituted pyrido[1,2-a][1,3]benzimidazole (1,3,4) are obtained analogously to example 5. Physico-chemical characteristics Zam is Albu, equipped with stirrer, thermometer, reflux condenser and capillary to enter argon, download C12H7N32.2 g (0.01 mol) 4, 3.8 g (0.01 mol) of rhodamine 123 and 10 g of phenol. The resulting mixture was slowly heated with stirring to 175...185°C. the Resulting melt is maintained with stirring in a stream of argon prior to the termination of excretion of ammonia. After the reaction, the reaction mixture was poured into 20 ml of ethanol, and the precipitated precipitate is filtered off, washed with 3 ml of ethanol and dried at T=60°C for 2 hours. Obtain 10.3 g (94% of theory) of hexatriene.

Found, %: C 74,86; H 3,81; N 12,65

Calculated, %: C 74,58; N A 3.87; N 12,79: (C68H42N10O6)

The IR spectrum of hexatriene no band 2220 cm-1- C=N, there is a band at 680 cm-1- C=N-.

The structural formula of hexatriene obtained on the basis of 4 and rhodamine 123:

Macroheterocycles obtained on the basis of 4 and rhodamine 123 has the following spectral characteristics: the maximum of a spectrum of radiation - 578, 621, 709 nm at the maxima of the absorption spectrum - 301, 343, 430 nm.

The method of obtaining substituted pyrido[1,2-a][1,3]benzimidazole of General formula I

namely, that 2-nitro-4-R-5-R1-halogenase subjected to interaction with pyridine at a temperature of 20°C and a molar ratio of 1:7 and subsequent reduction with simultaneous cyclization of the resulting salt of N-(2-nitro-4-R-5-R1-phenyl)pyridinium General formula II

where X Is CL, Br;

R and R1have the above values,

by treating an alcoholic solution of the above salt solution of SnCl22H2O in 3% hydrochloric acid and a molar ratio salt of N-(2-nitro-4-R-5-R1-phenyl)pyridinium: Snl22H2O=1:3 at a temperature of 20°C for 0,12 o'clock



 

Same patents:

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

The invention relates to organic chemistry and can find application in medicine

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to the derivatives of imidazopyridine formula

or its pharmaceutically acceptable salts, where R1- H, CH3or CH2OH; R2- CH3CH2CH3; R3- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, halogen; R4- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or halogen; R5- H or halogen; R6, R7are the same or different and mean H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or C1-C6alkoxy-substituted C1-C6alkyl; X represents NH or O, which inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases

The invention relates to a method for producing 7-aminopyrido[1,2-a][1,3]benzimidazole of the formula (1), which can be used as an intermediate in the synthesis of fluorescent and biologically active substances

The invention relates to 7-chloro-4-hydroxy-2(2-chloro-4-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione, its pharmaceutically acceptable salts, methods for treating pain, when administered pain relieving effective amount of this compound, and pharmaceutical compositions containing this compound

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

Up!