The way to obtain 2,3-bis-koimeterion-1,2,3,4 - tetrahydroquinoxaline
(57) Abstract:Usage: in medicine as antimicrobial agents. The inventive products - 2-n-bromobenzonitrile-3-benzoylmethylene-1,2,3,4-tetrahydroquinoxalin. BF C24H17BrN2O2; so pl. 201 - S. 2-n-Nitrobenzylidene-3-benzoylmethylene-1,2,3,4-tetrahydroquinoxalin. BF C24H17N3O4so pl. 220 - S. Reagent 1: 2-n-bromobenzonitrile-5-phenyl-2,3-dihydro-3-furanone or 2-n-nitrobenzylamine-5-phenyl-2,3-dihydro-3-furanone. Reagent 2: o-phenylenediamine. Reaction conditions: an organic solvent, room temperature. The invention relates to the field of organic chemistry, to the class of heterocyclic compounds - derivatives of 1,2,3,4-tetrahydroquinoxaline, namely to a new way to obtain previously unknown connections - 2,3-bis-koimeterion - 1,2,3,4-tetrahydroquinoxaline formula
< / BR>(Ia, b) where R = Br(a), NO2(b) that may find application in medicine as drugs with antimicrobial action.A method of obtaining representatives of this class of compounds, for example, 2,3-bis-benzoylmethylene-1,2,3,4-tetrahydro - finokalia (II), which consists in the interaction of 2> is within 8 h in the presence of sodium hydride  scheme
< / BR>< / BR>Compound II obtained with a yield of 62% , based on spectral data, exists in solution in tautomeric form 2,3-bis-benzoylmethylecgonine.The disadvantages of this method include:
inability to obtain 2,3-bis-koimeterion-1,2,3,4 - tetrahydroquinoxaline I with different substituents in the benzene ring;
extended heating of the mixture of reagents (8 h) at a temperature of 85aboutWith the use of toxic and dangerous to handle sodium hydride as a catalyst for acylation, the low yield of the target finokalia II.The aim of the invention is to develop a simple implementation that is free from the above disadvantages of the method, allowing to obtain 2,3-bis-koimeterion-1,2,3,4-tetrahydroquinoxaline formula I. Expected from the use of the present invention, the positive effect is that underlying the invention, the method of synthesis of the target compounds I is preparative and can be widely used in laboratory and industrial conditions of synthesis of biologically active substances, including drugs with FR is anony (IV and b) is subjected to interaction with o-penitentiaries in the environment of an organic solvent at room temperature according to the following scheme
< / BR>where I, IV : R = Br(a), (BO2(b), and produce target products I a, b known techniques.The compounds I and b represent orange crystalline substance, soluble in acetic acid, dimethyl sulfoxide, acetone, sparingly soluble in benzene, chloroform, ethanol and insoluble in water and hexane.This reaction underlying the proposed method is unexpected, as close to methylanthracene IV on the structure of 5-aryl-2-methoxycarbonylmethylene-2,3-dihydro-3-furanones interact with o-phenylenediamine with the formation of other compounds - products attach amine 2-eksootilisemaid communication reagents 3-(5-aryl-2,3-dihydro-3-furanone-2-yl) -1,2,3,4 - tetrahydro-2-hinoksolinov.The formation of 2-koimeterion-3-methoxycarbonyl-1,2 - dihydroquinoxaline by the reaction of 2-aryl-2 - methoxycarbonylmethylene-2,3-dihydro-3-furanone with o-phenylenediamine occurs only when heated in the presence of catalytic amounts of hydrochloric acid.The invention is illustrated by the following examples.
aboutC.Found, % : C 64,92; N 3,60; Br 18,17; N 6,25.WITH24H17BrN2O2.Mol. weight 445,31.Calculated, % : C 64,73; N 3,85; Br 17,94; N 6,29.IR spectrum , cm-1(the crystals): 1580-1595 (WITH the chelate. , Ar).Range of PMR, , M. D. , CDCl3: 6,47 c(IH, CH), 6,52 c (lH, CH), 7,20 (2H, 2NH), at 7.55-8.00 m(I3H,6H5,2C6H4). Mass spectrum, 95aboutWith the shown peaks of ions with 81Br, m/z : 446 M+, 418 M-CO+, 341 M-C6H5CO+, 262 M-4-BrC6H4CO+, 185 4-BrC6H4CO+, 157 4-BrC6H4+or M-4-BrC6HCO - C6H5CO+, 130 , IO5 C6H5CO+, 77 C6H5+.Honokalani I can't have the structure of the isomeric 2-aroyl-acetyl-4-aryl-IH-1,5-benzodiazepine (A), as in the mass spectrum of compound Ia no peaks ions benzonitrile (m/z 103) and p-bromobenzonitrile (m/z 183), but there are intense peaks sensornogo (m/z 105) and p-bramasole (m/z 185) ions.< / BR>When carrying out the reaction with the same kalvehed target product Ia is 1.50 g (67% ).P R I m e R 3. When using as solvent chloroform - output connection Ia 1.70 g (76% ).P R I m e R 4. 2-p-Nitrobenzylidene-3-benzoylmethylene-1,2,3,4 - tetrahydroquinoxalin (IB).To a solution of 2.06 g (0,005 mol) 2-p-nitrobenzylamine-5-phenyl - 2,3-dihydro-3-furanone IV in 200 ml of ethanol at room temperature, add with stirring a solution of 0.54 g (0,005 mol) of o-phenylenediamine in 50 ml of ethanol. The solvent is evaporated, the residue is recrystallized from ethyl acetate. Get 1,74 g (66% ) of crystalline compound IB with so pl. 220-221aboutC.Found, % : C 70,19; N. Of 4.04; N 10,32.WITH24H17N3O4. M 411,41.Calculated, % : C 70,07; N 4,16; N Of 10.21.IR spectrum , cm-1(the crystals): 1580-1593 (WITH the chelate. , Ar). Range of PMR, , M. D. , DMCO-D6: 7,02 (IH, CH), 7,12 c(IH, CH), 7,70-8,05 m (13H, WITH6H5, 2C6H4), 8,43(2H, 2N).Spectral data were consistent with the structure of the compounds Ia, b.The practical significance of 2,3-bis-koimeterion-1,2,3,4 - tetrahydroquinoxaline Ia, b is their antimicrobial activity. Thus, compound Ia has a strong bacteriostatic activity against reference strains of Golden starice growth of these bacterial cultures with a minimum inhibitory concentration (MIC) of the substance to 1000 µg/ml.The proposed method of producing 2,3-bis-koimeterion-1,2,3,4 - tetrahydroquinoxaline formulas Ia, b has the following advantages:
simple to perform, does not require continuous heating of the reaction mixture, the target products are formed in high yield;
eliminates the use of toxic and dangerous to handle reagents;
provide a wide range of previously unknown 2,3-bis-koimeterion-1,2,3,4-tetrahydrobenzo - Linova, including with different substituents in the benzene rings, which cannot be obtained by known methods.Thus, the way to obtain 2,3-bis-koimeterion-1,2,3,4 - tetrahydroquinoxaline can be used both in laboratory and industrial conditions of synthesis of biologically active substances. (56) 1. Wolfe I. F. et al. "Synthetic and Mechanisfic Aspeets of the sodium Hydride promoted Acylation of Methylated Heteroaromatics", J. Org. Chem, 1974, v. 39, No. 14, p. 2006-2010.2. USSR author's certificate N 1324261, C 07 D 405/04, 1985.3. USSR author's certificate N 1606509, CL 07 D 241/42, 1989. The WAY to OBTAIN 2,3-BIS-KOIMETERION-1,2,3,4-TETRAHYDROQUINOXALINE General formula
< / BR>where R is Br, NO2,
characterized in that the corresponding 2-aroyl is orites at room temperature.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.
EFFECT: valuable medicinal properties of compounds and composition.
10 cl, 8 tbl, 35 ex
FIELD: organic chemistry, biochemistry, enzymes.
SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.
EFFECT: valuable medicinal and biochemical properties of compounds.
24 cl, 13 sch, 4 tbl, 15 ex
SUBSTANCE: invention refers to 1,4-di-N-oxide-2,3-di(chloromethyl)quinoxaline process by halogenations of 1,4-di-N-oxide-2,3-dimethylquinoxaline in hydrochloric and acetic acid medium. Halogenating agent is gaseous chlorine or chlorine in statu nascendi. The process temperature is 70-95°C.
EFFECT: new compounds are characterised with useful biological activity.
3 cl, 5 ex
SUBSTANCE: invention relates organic chemistry and specifically to novel pyridine amide derivatives of general formula I where n equals 1; R1 and R2 together denote a residue selected from a group consisting of -CH=N-NH- and -CH=CH-N=CH-, which is bonded in any desirable direction to the parent structure or R2 and R3 together denote a residue selected from a group consisting of -CH=N-NH-; -CR28=N-NH-; -S-C(=S)-NH-; -S-CR29=N-; -N=CR30-O-; -N=CH-NH-; -N=N-NH-; -O-CH2-O-; -CH2-CH2-CH2-NH, -O-CH2-CH2-O-; -N=CH-CH=N-; -CH=CH-CH=N-, which is bonded in any desirable direction to the parent structure, or R3 and R4 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, or R4 and R5 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, and the rest of the residues R1, R2, R3, R4 and R5, mutually independently, in each case denote H; where R28 denotes F; Cl; Br or I; R29 and R30, mutually independently, in each case denote -NH-C(=O)-R31; -NH2; -NH-S(=O)2-R32; -NH-C(=O)-O-R33; -S-R34; where R31, R32, R33 and R34, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R6 denotes H or denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R7 denotes hydrogen or -OH; R denotes -CF3; or denotes an unsubstituted tert-butyl residue; T denotes C-R35 and U denotes C-R36, V denotes N and W denotes C-R38; where R35 and R36 denote H; where R38 denotes -NR40R41; -OR42 or -SR43; where R40, R41, R42 and R43, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; or denote a saturated, unsubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-member cycloaliphatic residue, or where R40 and R41 in each case together with a nitrogen atom as a ring member which binds them together, form a saturated 6-member heterocycloaliphatic residue, optionally substituted with one R57 residue, where R57 denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; in each case in form of corresponding physiologically acceptable salts. The invention also relates to a method of producing a compound of formula I, a medicinal agent based on the compound of formula I and use of the compound of formula I.
EFFECT: obtaining novel amide derivatives of pyridine, useful in treating vanilloid receptor 1 mediated diseases.
25 cl, 1 tbl, 18 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to application of formula
where stands for aromatic ring, where V represents C or N and, where V represents N, V is in meta- or para-position to Z, R independently represents hydrogen atom, halogen atom or group, selected from group -CN, hydroxyl group, group -COOR1, (C1-C3)fluoroalkyl group, (C1-C3)fluoroalkoxy group, group -NO2, group -NR1R2, (C1-C4)alkoxy group, phenoxy group and (C1-C3)alkyl group, where said alkyl is possibly monosubstituted with hydroxyl group, R1 and R2 independently represent hydrogen atom or (C1-C3)alkyl group, n equals 1, 2 or 3, n' equals 1 or 2, R' represents hydrogen atom, halogen atom or group, selected from (C1-C3)alkyl group, group -NO2, group -NR1R2, morpholinyl group, N-methylpiperazinyl group, (C1-C3)fluoroalkyl group and (C1-C4)alkoxy group, R" represents hydrogen atom, Z, Y, X, W, T, U independently represent N or C, and where maximum four of groups V, T, U, Z, Y, X and W represent N, and at least one of groups T, U, Y, X and W represents N, or any of its pharmaceutically acceptable salts for obtaining medication for prevention, inhibition or treatment of cancer. Invention also relates to application of particular compounds, to novel quinoline and isoquinoline derivatives, pharmaceutical composition based on novel quinoline and isoquinoline derivatives.
EFFECT: obtained are novel quinoline and isoquinoline derivatives, and novel biological activity of known compounds is discovered.
10 cl, 2 tbl, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to using a compound of formula
or any of its pharmaceutically acceptable salts, wherein means an aromatic ring, wherein V represents C or N, and when V represents N, V is found in meta- or para-position to Z, R independently represents a hydrogen atom, halogen atom or group specified in -CN group, hydroxyl group, -COOR1 group, (C1-C3)fluoralkyl group, (C1-C3)fluoralkoxy group, -NO2 group, -NR1R2 group, (C1-C4)alkoxy group, phenoxy group and (C1-C3)alkyl group, wherein the above alkyl is optionally monosubstituted by a hydroxyl group, R1 and R2 independently represent a hydrogen atom or (C1-C3)alkyl group, n is equal to 1, 2 or 3, n′ is equal to 1 or 2, R′ represents a hydrogen atom, halogen atom or group specified in (C1-C3)alkyl group, -NO2 group, -NR1R2 group, morpholinyl group, N-methylpiperazinyl group, (C1-C3)fluoralkyl group and (C1-C4)alkoxy group, R″ represents a hydrogen atom, Z, Y, X, W, T and U represent N or C, and wherein at most four of V, T, U, Z, Y, X and W groups represent N, and at least one of T, U, Y, X and W groups represents N, for producing a medicinal preparation for preventing, inhibiting or treating AIDS. The invention also refers to using specific compounds, new quinoline derivatives, a pharmaceutical composition based on the new quinoline derivatives.
EFFECT: new quinoline derivatives are produced, and new biological activity of known compounds is stated.
15 cl, 2 tbl, 11 ex
SUBSTANCE: invention relates to organic chemistry, specifically to a heterocyclic compound of formula (IA) or to a pharmaceutically acceptable salt thereof, where in each case R1 and R3 are independently selected from a group comprising hydrogen, halogen, -OH, -C1-2alkyl, -O-C1-2alkyl, -O-C1halogenalkoxy, -N(C1alkyl)2; R2 represents hydrogen; W represents a group selected from -CH= or -N=; X represents a group selected from -CH=CH- or -N=CH-, where nitrogen from -N=CH- is directly bonded with ring 'a'; Y represents a group selected from -CH=CH- or -C≡C-; Z denotes a bond or group selected from -(CH2)n- and -CH=CH-; A is a group selected from -OR, -O(CH2)nphenyl, -O(CH2)nthiophene; P is selected from a group comprising -O-; Q is a group selected from -COOH; where R is selected from a group comprising hydrogen, -C1-6alkyl, -C3-6cycloalkyl, -C1alkyl (C3-6cycloalkyl), -C3-6alkenyl and -C3-6alkynyl; 'n' in each case represents an integer, selected from 1, 2 or 3; 'm' in each case represents an integer, selected from 0-3, inclusive. Invention also relates to a compound of formula (Id), where radicals are described in patent claim.
EFFECT: obtaining novel heterocyclic compounds effective as antagonists of cysteinyl-leukotriene.
9 cl, 1 dwg, 2 tbl, 67 ex
SUBSTANCE: invention relates to benzopyrazine derivatives of the general formula (I)
including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof, wherein W is -N(R3)-; R2 is C1-4alkoxy; Y is -CR18=N-OR19 or -E-D; E is bond, C2-4alkynediyl, -CO-(CR22R23)s-, -NR22-(CR22R23)s-, -(CR22R23)s-CO-NR22-(CR22R23)s- or -(CR22R23)s-NR22-CO-(CR22R23)s-; D is phenyl, 3-6 membered cycloalkyl or 5-9 membered mono- or bicyclic saturated, partially saturated or aromatic heterocyclyl containing 1-4 heteroatoms selected from N, O or S, wherein the said phenyl, cycloalkyl and heterocyclyl can each optionally being substituted with 1-2 R1-groups; with the exception of the compounds indicated in the formula; R1 is halogen, cyano, C1-6alkyl, C1-6alkoxy, -C(=O)-O-C1-6alkyl, hydroxyC1-6alkyl, -NR4R5 , C1-6alkyl substituted by -O-C(=O)-C1-6alkyl, C1-6alkyl substituted by -NR4R5, -C(=O)-NR4R5, R6, C1-6alkyl substituted by R6, -C(=O)-R6; R3 is halogenC1-6alkyl, optionally substituted by -O-C(=O)-C1-6alkyl, hydroxyC1-6alkyl, hydroxyhalogenC1-6alkyl, C1-6alkoxyC1-6alkyl, where each C1-6alkyl may optionally be substituted by one hydroxyl group or -O-C(=O)-C1-6alkyl, C1-6alkyl substituted by R9, C2-6alkynyl substituted with R9, C1-6alkyl substituted by -NR10R11, C1-6alkyl substituted by -O-C(=O)-NR10R11; R4 and R5 are hydrogen, C1-6alkyl, C1-6alkyl substituted by -NR14R15, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, where each C1-6alkyl may optionally be substituted by one hydroxyl group, -C(=O)-NR14R15, -C(=O)-O-C1-6alkyl, -C(=O)-R13; R6 is a 6-membered saturated or aromatic monocyclic heterocyclyl having 1 to 2 heteroatoms selected from N or O; the said heterocyclyl is optionally substituted by 1 substituent selected from C1-6alkyl, halogen, C1-6alkyl-O-C(=O)-; R9 is C3cycloalkyl or 3-6 membered monocyclic saturated, partially saturated or aromatic heterocyclyl containing 1-2 heteroatoms selected from N or O, the said heterocyclyl is optionally substituted by 1 substituent selected from =O, hydroxyC1-4alkyl, C1-4alkyl-C(=O)-, C1-4alkyl substituted by -NR14R15, C1-4alkoxy; R10 and R11 are hydrogen, C1-6alkyl, halogen C1-6alkyl, hydroxyC1-6alkyl or C1-6alkyl substituted by carboxyl; R13 is a saturated 6-membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from N and O; R14 and R15 are hydrogen or C1-4alkyl; R18 and R19 are C1-6alkyl; R22 and R23 are hydrogen; n=2; s=0, 1, 2, or 3. Invention also relates to a pharmaceutical composition and a product based thereon, the use of a compound of formula (I) and a method of prevention or treatment of conditions mediated by FGFR kinase.
EFFECT: new derivatives of benzopyrazine, useful for cancer treatment.
28 cl, 4 tbl, 54 ex