The method of obtaining polycyclic biocidal compounds or their salts
(57) Abstract:The inventive product - polycyclic biocidal compounds of General f-ly Ar CH2Other, where Ar is 2-benzo/b/oil /2,1-d/ thiophene-5-yl; 2-benzo/b/ oil/2,3-d/furan-6-yl; 2-benzo-/b/oil/1,2-d/furan-5-yl; 2-(7-methyl-7H-benzo/c/carbazole-10-yl)methyl; 2-/benzo/b/oil/2,1-d/furan-5-yl; R-C(CH3) (CH2OH)2or their salts. Reagent 1: compound f-ly Ar CHNR, where R, Ar is as defined above; Reagent 2: the restorer. table 2. The invention relates to heteroalicyclic alkanols derived, and in particular to methods of obtaining new polycyclic biocidal compounds of General formula I
ArCH2Other where Ar is 2-benzo/b/oil/2,1-d/thiophene-5-yl; 2-benzo/db/oil/2,3-d/furan-6-yl; 2-benzo/b/oil/1,2-d/furan-5-yl; 2-/7-methyl, 7H-benzo/with/carbazole-10-yl/methyl, 2-/benzo/b/oil/2,1-d/furan-5-yl; R= - H3or their salts, which can be used as anticancer agents.Known (1-nitro-9-[(3-dimethylaminopropyl)-amino]-acridine) containing 2-amino-2-methyl-1,3-propandiol and Tris(oxymethyl)-methylaminopropyl with antitumor action.However, among heteroalicyclic aromatic alkanols derived anticancer drugs nicheskij aromatic alkanols derivatives, with antitumor activity with less toxicity for warm-blooded.This goal is achieved by a method of obtaining compounds of General formula I by the reduction of compounds of General formula
(II) ArCHNR, where Ar and R above.P R I m e R 1. 2-[Benzo/b/oil/2,1-d/thiophene-5-ylmethyl/-amino]-2-methyl-1,3-propertiesmetaltheme.In a round bottom flask equipped with a magnetic stir bar, a refrigerator, a thermometer, a trap Dean-stark tube for nitrogen and a bubbler, download 4.94 g of benzo/b/oil/2,1-d/thiophene-5-carbaldehyde (18,83 mmol), 1.98 g of 2-amino-2-methyl-1,3-propane diol (18,83 mmol), 0.1 g of p-toluenesulfonic acid monohydrate and 200 ml of toluene. The mixture is stirred at the boiling temperature with removal of water for 2.5 hours, or until no longer water, which is extracted with 3 portions of 500 ml of ethyl acetate. An ethyl acetate extracts are collected. A large part of the toluene is then removed by distillation. The mixture is then cooled in a bath with ice and diluted with 200 ml of absolute ethanol, and then further cooling. In the reaction mixture in one portion add 0,712 g of solid Na borohydride (18,83 mmole). Next, bath with ice is removed, the reaction mixture is at what Laney acid in a rotary evaporator to remove the solvent. The crude solid product is subjected to shaking in 300 ml of 1 N. hydrochloric acid, filtered off, washed with hydrochloric acid, subjected to vacuum filtration to a moist condition and washed with 300 ml of diethyl ether. Then the material is dissolved in 200 ml of methanol, filtered the solution and alkalinized 1 l of 1 n solution of hydrate of sodium oxide. The washing liquid with the solid white material combine, filtered, washed with 3 portions of 500 ml of saturated sodium chloride solution, dried over 25 g of potassium carbonate, filtered and concentrated in a rotary evaporator to obtain a white solid product. This latter dissolved in a mixture of 200 ml of absolute ethanol with 3 ml of methansulfonate, the solution is filtered and diluted to a volume of 4 liters of a mixture of diethyl ether and hexane in a ratio of 1: 1. This material is recrystallized three times from ethanol-hexane in the ratio of 1:3, resulting in a gain 2-/benzo/b/oil/2,1-d/thiophene-5-yl-methyl/-amino-2-me-til-1,3 - propertiesmetaltheme with so pl. 221-222aboutWith that put an exact analysis for determining the structure of carbon, hydrogen, nitrogen and sulphur.P R I m m e R 2. 2[/benzo/b/oil/2,3-d/furan-6-ylmethyl-amino]-2-Mattara described in example 1, from benzo/b/oil/2,3-d/furan-6-carbaldehyde and 2-amino-2-methyl-1,3-propane diol get 2-[/benzo/b/- oil/2,3-d/furan-6-ylmethyl/-amino] -2-methyl-1,3 - propertiesmetaltheme. 0,4 H2About including square 187-190aboutWith (a mixture of ethanol-diethyl ether), which is subjected to the exact analysis for determining the structure of the elements carbon, hydrogen, nitrogen and sulphur.P R I m e R 3. 2-[Benzo/b/oil/1,2-d/furan-5-ylmethyl/-amino]-2-methyl-1,3 - propertiesmetaltheme.Using the procedure of restorative amination described in example 1, benzo/b/oil/1,2-d/-furan-5-carbaldehyde and 2-amino-2-methyl-1,3-propane diol get 2-[/benzo/b/oil/1,2-d/furan-5-ylmethyl/-amino]-2-me - til-1,3 - propertiesmetaltheme with melting point 215-217aboutWith (a mixture of ethanol-diethyl ether), which is subjected to the exact analysis for determining the structure of the elements carbon, hydrogen, nitrogen and sulphur.P R I m e R 4. 0,3-hydrate-2-methyl-2-[(/7-methyl-7H-benzo/with/carbazole-10-yl/-methyl)-amino]- 1,3-propeciageneric.The specified connection get in the way similar to described in example 1 from 7-methyl-7H-benzo/c/carbazole-10-carbaldehyde and 2-amino-2-methyl - 1,3-propane diol; its so pl. is 229-230aboutWith (razloga is 0; H Is 6.61; N 7,18; Cl Remaining 9.08.C22H15N2O2Cl.0,3 H2O
Found,%: C 67,61; H 6,53; N 7,17; Cl 9,05.This structure was consistent with the NMR spectrogram.P R I m e R 5. 2-[benzo/b/oil/2,1-d/furan-5-ylmethyl/-aminomethyl]-1,3-propandiol.According to methods similar to described in example 1 using benzo/b/oil/2,1-d/- furan-5 - carboxaldehyde and 2-amino-2-methyl-1,3-propane diol got mentioned in the title compound in the form of methane - sulphonate salt so pl. 216-218aboutWith (a mixture of ethanol with diethyl ether in the ratio 1:1).Calculated, %: C 60,23; H To 5.93; N 3,19; S 7,31.C22H25NO6S.Found,%: C 60,22; H To 5.93; N 3,18; S 7,30.These NMR spectrum was consistent with this structure.Test lymphoid leukemia R/0.For this test as experimental animals used mice DM2-F1 single-sex weighing 20 3 g / day 0 animals as the control group and the group that was exposed to treatment, intraperitoneal injection was administered a suspension of 106living tumor cells R/0. During each test was evaluated by several dosages, which cover also has Polzovali in the form of drugs or physiological solution, which contained 0.05% product Turen-80, or in distilled water that contained 5% dextrose, and these drugs were injected intraperitoneally on the 1st, 5th and 9th days in relation to implantation of tumor cells. Dosage was calculated in mg/kg based on the mass of each individual animal; recorded the day of death of each animal was calculated averages for each group of animals, as well as the magnitude of the ratio of the average life expectancy of the animal groups treated (T) and control groups (). The criterion of activity of the compounds was determined by the formula T/Sh 120%. The results of the tests with R/0 are given in table.1 and 2.Compounds according to the invention result in a significantly larger number of 30-day survivors of individuals than the reference compound.Another advantage of the compounds I is their lower toxicity. The method of obtaining polycyclic biocidal compounds of General formula
where Ar is 2-benzo(b)oil(2,1-d)thiophene-5-yl, 2-benzo(b)oil(2,3-d)furan-6-yl, 2-benzo(b)oil(1,2 - d)furan-5-yl, 2-[7-methyl - 7H - benzo(c)carbazole - 10 - yl]methyl, 2- [benzo(b)oil(2,1 - d]furan - 5 - yl;< / BR>R- - H3< / BR>or their salts, different tyuleniy.
FIELD: organic chemistry, medicine, endocrinology.
SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.
EFFECT: valuable medicinal properties of compounds.
11 cl, 41 tbl, 243 ex
SUBSTANCE: invention relates to production of heterocyclic ketones of formula or or their mixes, wherein R1 and R2 are hydrogen, alkyl, C6-C10 aryl; or R1 and R2 together form cyclic ring system;R3 C1-C40 alkyl; X sulfur; by interaction of heterocyclic compound of the formula (II) with α, β-unsaturated carboxylic acid or with anhydride of an acid in a liquid reactionary medium which includes a strong organic acid selected from the group includingC1-C8 alkylsulfonic acid and a water absorber selected from the group including phosphorus pentoxide, a strong organic acid possessing higher acidity, compared to carbolyxic acid; the process is effected by adding simultaneously the compounds of formula (II), acids or anhydride to the reactionary medium specified above, at temperature from 50 to 110°C. Replaced heterocyclic ketones make the important initial compounds on receiving heterocyclic metallocene catalysts for polymerization of α-olefines.
EFFECT: new compounds possess useful biological properties.
5 cl, 2 tbl, 5 ex
FIELD: chemistry, pharmacology.
SUBSTANCE: claimed invention relates to sulfamate derivatives of benzothiophene, obtained by method including stages: 1) conversion of 6-methoxybenzothiophene (3); , where R3 represents monobromine-derivative using N-bromosuccinimide and APTS in standard conditions; 2) conversion of said monobromine-derivative by interaction with Mg in Et2O in argon atmosphere into magnesium-organic bromide and its further condensation with ketone or aldehyde selected from group, consisting of cyclopentanone, cyclohexanone, cycldecanone, 4-methylcyclohexanone, 2-methylcyclohexanone, 2,2-dimethylcyclopentanone, 2-adamantanone, propanal, hexanal, cyclohexane carboxaldehyde, cycloheptancarboxaldehyde in Et2O obtaining corresponding hydroxyl-substituted methoxybenzothiophene in standard conditions; 3) processing said hydroxy-substituted methoxybenzothiophene with triethylsilane in argon atmosphere in dichlomethane obtaining corresponding substituted methoxybenzothiophene; 4) optional alkylating of corresponding substituted methoxybenzothiophene using standard conditions obtaining corresponding substituted methoxybenzothiophene, carrying (C1-C6)alkyl or (C3-C12)cycloalkyl; removal of protective group from substituted methoxybenzothiophene, obtained at stage 3) or stage 4) in presence of tribromborane in standard conditions; conversion of obtained hydroxy-compound into corresponding sulfamate by processing with sodium hydrate and amidochlorsulfonic acid, or interaction with sulfamoylchloride in dimethylacetamide; 7) optional oxidation of obtained compound with hydrogen peroxide in trifluoracetic acid in standard conditions. Compounds can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders. Also described are pharmaceutical composition based on compounds I and application of the latter.
EFFECT: obtaining compounds which can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders.
43 cl, 1 dwg, 10 tbl, 67 ex
SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):
, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.
EFFECT: obtaining a pharmaceutical composition based on the said compounds.
8 cl, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a method for preparing 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts which involves the use as a parent compound, (phenylthio)acetic acid derivative or its salts presented by general formula: where X1 represents halogen atom, and is applicable as a safe method of volume production of 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts effective as an agent in disorders of the central nervous system and peripheral nervous system.
EFFECT: there is provided high yield, safety for human body, low environment loads.
36 cl, 1 tbl, 33 ex
SUBSTANCE: invention relates to a heterocyclic compound or salt thereof, having formula (1): where R2 is hydrogen or a lower alkyl group; A is a lower alkylene group or a lower alkenylene group and R1 is a cyclo(C3-C8)alkyl group, an aromatic group or a heterocyclic group selected from a group consisting of groups (I)-(IV), defined in the formula of invention. The invention also relates to a pharmaceutical composition, having activity as a partial agonist of dopamine D2 receptors and/or a serotonin 5-HT2A receptor antagonist and/or an adrenalin α1 receptor antagonist and/or a serotonin absorption inhibitor and/or serotonin reuptake inhibitor based on said compounds, a method of preparing a pharmaceutical composition, use of said compounds as a partial agonist of dopamine D2 receptors and/or a serotonin 5-HT2A receptor antagonist and/or an adrenalin α1 receptor antagonist and/or a serotonin absorption inhibitor and/or serotonin reuptake inhibitor, as well as a method of producing formula I compounds.
EFFECT: novel compounds are obtained and described, which have a wide range of curative effect on mental disorders, including central nervous system disorders, without side effects and with high degree of safety.
22 cl, 3110 ex, 314 tbl
SUBSTANCE: invention relates to sulphamate derivatives of benzothiophene of formula or
where R1, R2, R3, m and n assume values given in the claim.
EFFECT: possibility of use in treating oestrogen-dependent diseases.
38 cl, 63 ex, 10 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a method for preparing a compound of general formula VIII of enantiomeric purity min. 80% by a reaction of the compound according to general formula IV with enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid to produce a compound of general formula II to be reduced to prepare a compound for general formula I to be oxidated to form an aldehyde which then reacts with an aromatic amine of formula H2N-Ar to produce a respective imine which is then reduced to prepare a compound described by formula VIII in the enantiomeric pure form. Also, it refers to methods for preparing the compound of formula I, as well as to the compounds of formula I. In general formulas
, , X1, X2, X3 is specified in fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, trifluoromethyl, amino whereas the other groups X1, X2, X3 represent a hydrogen atom.
EFFECT: preparing the non-steroid anti-inflammatory drugs.
12 cl, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to compound of structural formula
which can be applied for treatment, prevention or carrying out treatment of neurological disorder. In formula (Iva) m is equal 0; n is equal 1; R1 and R2 are, each independently, hydrogen, C1-C4alkyl or C3-C6cycloalkyl; R3 and R4 are, each independently, hydrogen or C1-C4alkyl; R5 is hydrogen and R6 and R7 are, each independently hydrogen, halogen, C1-C4alkyl, C6-C10aryl, 5-10-membered heteroaryl, which contains one O atom, one S atom and/or 1-4 N atom(s), 3-8-membered heterocyclyl, containing 1-2 heteroatoms, selected from O, S and N, C1-C4alcoxyl or aminoC1-C4alkyl.
EFFECT: invention relates to pharmaceutical industry, which contains claimed compound, and to method of treatment, prevention or carrying out of treatment of neurological disorder such as psychosis or schizophrenia.
54 cl, 2 tbl