Adamantane amino-derivatives having influenza virus inhibiting activity
SUBSTANCE: in adamantane amino-derivatives of general formula (1), R=OH, R1=R2=R3=H, R4=C2H5, X=Cl, n=1 (I); R=Br, R1=R2=R3=H, R4=C2H5, X=Br, n=1 (II); R=OH, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Cl, n=1 (III); R=Br, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Br, n=1 (IV); R=OH, R1=R2=CH3, R3=R4=H, X=CI, n=1 (V); R=CH3, R1=-CH2OH, R2=R3=R4=H, X=Cl, n=1 (VI).
EFFECT: higher antiviral activity of derivatives towards influenza virus.
1 cl, 1 tbl, 9 ex
The invention relates to the field of biologically active compounds, medicine, in particular of Virology and chemotherapy of viral infections, and can be used to suppress the reproduction of influenza viruses and the reduction caused by disease.
Famous hydrochloride 1-aminomethyl-and-methyladenine (rimantadine) [1, 2], effectively suppressing the reproduction of influenza viruses and is used in several countries as a means of treatment and prevention of influenza. Lack of rimantadine is relatively low activity .
A wider range of non-toxic concentrations (doses) with antiviral action has hydrochloride 1-aminoadamantana (amantadine) , (adopted for the prototype), also used as a medicinal antiviral drug. The disadvantage of amantadine is significant side effects on the Central nervous system and reduced in some cases the activity .
Object of the invention is the extension of the range of agents with antiviral action.
This object is achieved by the use of amino adamantanol number of General formula
where R=OH, R1=R2=R3=H, R4=C2H5X=Cl, n=1 (I);
R=Br, R1=R2=R3=H, R4=C2H5X=Br, n=1 (II);
R=OH, R1=R2=H, R3+R4 2CH2CH2CH2-, X=Cl, n=1 (III);
R=Br, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Br, n=1 (IV);
R=OH, R1=R2=CH3, R3=R4=H, X=Cl, n=1 (V);
R=CH3, R1=-CH2OH, R2=R3=R4=H, X=Cl, n=1 (VI);
R=R1=R2=R3=H, R4=-CH2CH2NH2, X=Cl, n=2 (VII)
possessing activity against the reproduction of influenza virus.
The authors found a non-obvious property that allows it to apply the derivatives of adamantane as inhibitors of reproduction of influenza virus. The technical result of the invention are new chemical compounds with high selectivity index of antiviral action. In the patent and scientific literature information about the claimed compounds and their biological activity is absent.
Disclosure of the invention. The recovery of 1-hydroxy-3-acetylaminofluorene receive hydrochloride 3-N-ethylamino-1-hydroxyadamantane. The interaction of 3-N-ethylamino-1-hydroxyadamantane with Hydrobromic acid gives the hydrobromide of 1-bromo-3-N-ethylaminoethanol. The recovery of N-(1-hydroxy-3-substituted)-γ-butyrolactam lithium aluminum hydride synthesized N-(1-hydroxy-3-substituted)pyrrolidin, isolated as hydrochloride. The interaction of N-(1-hydroxy-3-adamant the l)pyrrolidine bromide with tiomila obtained N-(1-bromo-3-substituted)pyrrolidin the hydrobromide. Alkaline hydrolysis of 1-acetylamino-3,5-dimethyl-7-adamantanol and 1-acetyl amino-3-acetoxymethyl-5-methylguanine obtained the corresponding 1-amino-3,5-dimethyl-7-adamantanol hydrochloride and 1-amino-3-hydroxymethyl-5-methylalanine hydrochloride. N-(1-Substituted)Ethylenediamine synthesized by the reaction of 1-bromoguanine with Ethylenediamine and subsequent isolation of the product in the form of the dihydrochloride.
3-N-Ethylamino-1-hydroxyadamantane hydrochloride (compound I):
To a suspension of 0.13 mole of lithium aluminum hydride in 50 ml of tetrahydrofuran is added to 0.016 mol of 1-hydroxy-3-acetylaminofluorene. The reaction mixture is boiled with stirring for 20 hours Then added successively with 5 ml water, 5 ml of 40%sodium hydroxide solution, and then 15 ml of water. A solution of 1-hydroxy-3-N-ethylaminoethanol in tetrahydrofuran is separated from the inorganic salts, the solvent is distilled off, the solid residue is dissolved in benzene and let dry hydrogen chloride. The precipitate is filtered off, dried and recrystallized from isopropyl alcohol.
Yield 86%, So pl. 243-245°C.
IR spectrum, ν, cm-1: 3463 (NH), 3204 (OH), 2930 (CH, Ad), 2862 (NH), 2463 (NH), 1627 (NH), 1581 (NH), 1350 (HE), 1126 (C-N).
Found, %: C 61,90; N 9,40; N Of 5.92. Cl2H21NO·HCl. Calculated, %: C 62,19; N to 9.57; N6,04.
Mass spectrum (EI): m/z 195 (11%) [M]+, 180 (8%), 151 (7%), 138 (100%), 122 (27%).
1-Bromo-3-N-ethylaminoethanol g is dobromil (compound II).
1-Hydroxy-3-N-ethylaminoethanol in an amount of 0.014 mol dissolved in 10 ml of 63%Hydrobromic acid and left at room temperature. After 48 hours falls hydrobromide 1-bromo-3-N-ethylaminoethanol. The precipitate is filtered off and recrystallized from isopropyl alcohol. Yield 83%, TPL 275-278°C.
IR spectrum, ν, cm-1: 3404 (NH), 2930 (CH, Ad), 2817 (NH), 2478 (NH), 1311, 1164, 1076, 821.
Mass spectrum (EI): m/z 257(1%) [M]+, 178(100%) [M-Br]+, 122(66%).
Found, %: C 42,10, N 6,34, N 4,33. C12H20BrN HBr. Calculated, %: 42,50,
N 6,24, N4,13.
N-(1-Hydroxy-3-substituted)pyrrolidine hydrochloride (compound III)
To a suspension 0,084 mole of lithium aluminum hydride in 50 ml of tetrahydrofuran pin solution of 0.017 mole of N-hydroxy-3-substituted)-γ-butyrolactone in 100 ml of tetrahydrofuran. Boil with stirring for 7 hours was Added sequentially 3 ml of water, 3 ml of 40% solution of sodium hydroxide, 9 ml of water, separate the solution of N-hydroxy-3-substituted)pyrrolidine in tetrahydrofuran from inorganic salts, the solvent is distilled off, the solid residue is dissolved in dry benzene, through the benzene solution is passed a current of dry hydrogen chloride. Precipitated hydrochloride of N-hydroxy-3-substituted)pyrrolidine filtered, recrystallized from isopropyl alcohol. Yield 88%, TPL=240-242°C.
IR-spectrum (in Basel. oil), ν, cm _1: 3480, 2980, 2670, 1420. Mass spectrum (e is): m/z 221(21%) [M]+, 204 (5%), 178 (4%), 164 (100%), 148 (32%), 136 (6%).
Found, %: C 65,43, N 9,18, N 5,23. C4H23NO·HCl. Calculated, %: C 65,23, N 9,38, N5,43.
N-(1-Bromo-3-substituted)pyrrolidine hydrobromide (compound IV)
To 0.019 mole of the hydrochloride of N-(1-hydroxy-3-substituted)pyrrolidine slowly added 0,051 mol of methyl tiomila. Incubated at 20-25°C for 2 hours. Then upon cooling, add 10 ml of isopropyl alcohol to decompose the excess of methyl tiomila. The crystalline precipitate is filtered, recrystallized from water and then from isopropyl alcohol.
The yield is 50%, TPL=260-263°C.
IR-spectrum (KBr), ν, cm-1: 2933, 2565, 1461, 826.
Mass spectrum (EI): m/z 284(1%), 204 (100%), 148 (59%).
Found, %: C 45,90, N 6,34, N Of 3.73. C14H22BrNHBr. Calculated, %: 46,05, N 6.35mm, N 3,84.
1-Amino-3,5-dimethyl-7-adamantanol hydrochloride (compound V).
A mixture of 0.03 mol of 1-acetylamino-3,5-dimethyladamantane-7, 0.09 mole of potassium hydroxide, 2 ml of water and 17 ml of ethylene glycol boil for 40 hours. The reaction was poured into 200 ml of water, extracted with butanol. The extract was washed with 10 ml of water, evaporated to a volume of 30 ml, add hydrochloric acid to strongly acidic reaction, the hydrochloride of 1-amino-3,5-dimethyl-7-adamantanol extracted with diluted hydrochloric acid (1:10). The aqueous phase is brought to pH 10 with 40%sodium hydroxide solution, separated amine is extracted with butanol, extra is t washed with water, evaporated to a volume of 15 ml and saturated with gaseous hydrogen chloride. Then add 15 ml of acetone, the precipitated product is filtered and washed with acetone.
Yield 87%, TPL>300°C.
IR-spectrum (KBr), ν, cm-1: 3313 (HE), 2644 (NH), 2073 (NH), 1523 (NH), 1336 (HE), 1203 (NH), 624.
Mass spectrum (EI): m/z 195(8%) [M]+, 162 (4%), 138 (3%), 124 (100%). Found, %: C 61,60, N 9,24, N 5,73. C12H21NO·HCl. Calculated, %: C 62,19, N to 9.57, N6,04.
1 Amino-3-hydroxymethyl-5-methylalanine hydrochloride (compound VI).
A mixture of 0.05 mol of 1-acetylamino-3-acetoxymethyl-5-methylguanine, 0.1 mole of sodium hydroxide, 30 ml of ethylene glycol and 5 ml of water is boiled for 20 hours Then the reaction was poured into 200 ml of water and extracted with benzene. The benzene solution is dried with sodium sulfate, separated from the desiccant and saturated with dry hydrogen chloride. The precipitate is filtered off, dried and recrystallized from isopropyl alcohol.
Yield 69%, TPL>300°C.
IR-spectrum (KBr), ν, cm-1: 3446,2951 (SN, Ad). 2853, 2080, 1385, 1036. Mass spectrum (EI): m/z 195 (17%), 178 (4%), 164 (80%), 138 (38%), 108 (100%).
Found, %: C 61,61, N 9,34, N 5,79. C12H21NO·HCl. Calculated, %: C 62,19, To 9.57 N, N 6,04.
N-(1-Substituted)the Ethylenediamine dihydrochloride (compound VII):
A mixture of 0.056 mol of 1-bromoguanine, 50 ml of Ethylenediamine and 5 ml of water is boiled for 5 hours to dissolve 1-bromoguanine. Then the reaction mass is then cooled, volbu add 20 ml of benzene and 40%sodium hydroxide solution to dissolve the precipitate. After that, the organic layer separated, washed with water and concentrated hydrochloric acid. Hydrochloric acid solution is alkalinized to pH 12. The precipitation is extracted with benzene. The benzene extract is dried with sodium sulfate and saturated with hydrogen chloride. The precipitate is filtered off and dried.
Yield 83%, TPL 273-275°C.
IR spectrum, ν, cm-1: 3420 (NH); 2900 (CH, Ad); 2840 (NH2+), 1610 (NH++NH2+; 1450 (SN). 1070 (C-N).
Found, %: C 73,89; N 11,06; N 13,81. C12H22N2. Calculated, %: C 74,17; N 11,41; N14,42.
Mass spectrum (EI): m/z 194 (1%) [M]+, 177 (2%), 164 (38%) [M-CH2NH2]+, 151(3%), 135(100%) [Ad]+.
The study of the toxic properties of the claimed compounds.
The toxic properties determined by the ability to cause cytodestructive changes of cells after 72 h of incubation. Monolayer cell culture of primary trypsinization of fibroblasts of chicken embryos (FEC) is washed from the growth medium and to cause the breeding of amino adamantane on the environment support (medium 199) with a concentration of 800 μg/ml or less. Upon expiration of the specified period unpainted culture viewed at low magnification (X10 lens). The maximum tolerable concentration (MBC) adopt high concentration of substances that do not cause these changes. Establish that the compounds I, IV and V region is give the ability to cause cytodestructive cells in the concentration range from 400 μg/ml or less, compounds II and VII is in the range of concentrations of 100 μg/ml and below, compound VI is at a concentration of 50 μg/ml and below, the compound III is at a concentration of 12.5 μg/ml and below.
The antiviral activity of the claimed compounds.
The study was conducted by the method of reduction of the number of plaques under the agar surface. Monoclonal culture FEC grown in vials, washed from the growth environment, infect various dilutions of influenza virus A/FPV/Rostock/34 (H7N1) in the range from 0.01 to 0,00001 PFU/cell by applying vaccinated suspension in a volume of 0.1 ml for 1 h at 37°C. the liquid is Then removed and the cells are covered with molten nutrient coatings based on concentrate medium 199 supplemented with 1% of bactiera and 0.005% neutral red (all reagents Sigma) and different concentrations of the studied compounds. After hardening the coating on the bottles placed in a thermostat at 36 h and then count the number of plaques that are visible due to the presence in the coating of the vital dye. Based on the number of plaques calculate the titer of the virus. Criterion antiviral actions consider the existence of differences in comparison with control virus. Calculate the concentration of 50 and 95% suppression of viral replication (average effective and 95% effective concentration EC and ES respectively) and the relationship IPC/ES and IPC/ES (index selectivity).
P the obtained results are shown in the table.
Antiviral properties of synthesized compounds against influenza virus A/FPV/Rostock (H7N1)
As can be seen from the table, all investigated compounds effectively inhibit the replication of influenza virus in cell cultures. The widest range of effective non-toxic concentrations is connected VII (relationship IPC/EC50and IPC/EU95=385,8 and 18.5, respectively). Somewhat less he expressed the compounds II (relationship IPC/EU50and IPC/EU95=84,2 and 20.1, respectively) and I (relationship IPC/EU50and IPC/EC95=27,4 and 13.9, respectively). All of the claimed compounds exceed the comparator drug (amantadine) the ratio of IPC/EU95(index selectivity), and the connection I is also the ratio of IPC/EC50.
Thus, the inventive solution allows to solve the problem. When using the new amino derivatives adamantanol series manages to obtain a high selectivity of antiviral action against influenza virus. Used when performing studies with influenza virus A/FPV/Rostock (H7N1) is a model representative viruses of the genus Influenzavirus And when the study of the antiviral properties of synthetic and natural compounds , i.e. the presence and gibiruei properties in relation to the reproduction of the virus means, what activity spectrum of the analyte of interest applies to all influenza viruses A.
This property involves the use of the inventive compounds for the treatment and prevention of diseases caused by including highly pathogenic virus of avian influenza (H7N1) and A (H5N1).
The flu is most dangerous epidemic among infections caused by RNA genome viruses. In Russia annually more than 7 million cases of influenza infection, which is about 20% in the structure of infectious and parasitic diseases in the population. Feature of influenza virus (especially influenza) is the ability of the rapid emergence of new varieties due to antigenic variation. This is due to the complexity in the development of influenza vaccines, and become resistant to existing drugs of influenza virus strains. Influenza viruses of type a can infect not only humans, but some species of animals and birds, including chickens, ducks, pigs, horses, ferrets, seals and whales. Along with circulating in the human population by serotypes of influenza a (H3N2 and H1N1) serious concerns arise from avian viruses, which is the most pathogenic. The pathogens that cause highly pathogenic avian influenza viruses of subtypes H5 and H7 hemagglutinin. So, to date the avian flu is A(H5N1) causes the greatest number of cases of severe disease in birds fatal and potentially dangerous for people periodically there have been outbreaks of the disease, mainly by the staff of the poultry farms and persons closely in contact with poultry, including fatalities.
Highly pathogenic avian influenza is a very contagious disease that can cause 100% mortality of livestock. So, in 1983-1984, in the U.S. as a result of the outbreak of avian influenza was destroyed 17 million birds, and the economic damage amounted to $ 65 million. In 1999-2001 in Italy, the spread of the disease caused by the virus avian influenza(H7N1), led to the destruction of 13 million birds. Increasing cases of avian influenza A (H5N1) in Southeast Asia and other geographic regions, including on the territory of the Russian Federation, as well as the possibility of the emergence of this pathogen's ability to spread in the human population by respiratory (pathogen transmission from person to person) testify about the danger of a pandemic variants of this virus.
In addition, vaccination against highly pathogenic influenza a (H5N1) and A(H7N1) carries a huge risk of spreading the disease to other farms due to incomplete suppression of the infection. In this regard, many countries have imposed a ban on vaccination against avian influenza.
Therefore, the only means of combating these vozbuditel the mi is the creation of a highly effective chemotherapeutic drugs, having a high activity, bioavailability and low toxicity.
The identity of the virus of avian influenza a (H5N1) and A (H7N1) on the grounds of belonging to the same family and genus of viruses and caused disease, determines the fact that the drugs presented derived from a number of adamantane, effective for the treatment of infections caused by influenza a, including A (H7N1), also effective against virus a(H5N1) virus . As shown in the example of a study of amantadine and rimantadine in the spectrum antiviral action of anti-influenza drugs based on adamantane derivatives are most strains of influenza virus And human rights, including contemporary influenza viruses A(H3N2) and A (H1N1) [7-9].
The invention can be used in medicine and veterinary medicine. To develop final recommendations on the application of the inventive amino adamantane for the treatment and prevention of influenza, the necessary study of the safety, development of dosage forms, clinical (in-situ) testing and development of optimal schemes of application.
1. Prichard W.W. Adamantanes and tricyclo[220.127.116.11,8]undecanes. Pat. 3,352,912 USA. C07D 295/00 (20060101); C07D 295/03 (20060101); C07C 49/00 (20060101); C07C 49/323 (20060101).
2. Prichard, W. W. Pharmaceutical compositions and methods of controlling influenza A virus infection utilizing substituted adamantanes and tricycio[18.104.22.168'8]uridecanes. Pat,592,934 USA. C07D 295/03 (20060101); C07D 295/00 (20060101).
3. the opeko H., Pavlov NI Amantadine and rimantadine in the prophylaxis and treatment of influenza. The honey. news. - 1999. No. 3(47). - P.20-25.
4. Davies W.L. et al. Antiviral activity of 1-adamantanamine (amantadine). Science, 1964, V. 144, p. 862-863.
5. Votyakov VI, Boreco H., o Lord, Century and other Primary study of the antiviral properties of synthetic and natural compounds. The methodological. recommendations. Decl. UMC health Ministry of the USSR 28.05.86, Minsk, 1986, 26 S.
6. Lions D.K., Fedyakin I. T., Saltanov M., Prilipov A.G., Deryabin p. g, Galego GA Activity in vitro antiviral drugs on the reproduction of highly pathogenic strains of influenza virus a (H5N1)virus that caused the epidemic in poultry in the summer of 2005 the. virusol., 2006, t, " 2, P.20-22.
7. Grunert R.R., Hoffmann S.E. Sensitivity of influenza A/New Jersey/8/76 (Hsw1N1) virus to amantadine HC1. J. Inf. Dis., 1977, V. 136, No 2, p. 297-300.
8. Oxford J.S., G.C. Schild Inhibition of swine influenza virus A/New Jersey/76 (Hsw1N1) multiplication and polypeptide synthesis by amantadine. FEMS Environ. Letters, 1977, 1, p. 223-226.
9. The rotons M, Grebennikova T.V., Burtseva H., Shevchenko Y.S. Molecular-genetic analysis of epidemic strains of influenza a virus, characterized by different sensitivity to rimantadine, based on the nucleotide sequence of the M2 protein. The wedge. microbiol. antimicrob. hamiter., 2007, T. 9, No. 4, S-374.
The tool, which has antiviral activity against influenza virus, representing amino adamantanol number of General formula (1),
SUBSTANCE: invention relates to novel compounds of formula or to its pharmaceutically acceptable salts, where n is 0 or 1; R1 represents H or F; R2 represents C1-4alkyl; R7 represents H or C1-4alkyl; and Z represents hydroxyl C1-6alkyl or C1-6alkoxycarbonyl, or 5- or 6-member heteroaromatic ring, which belongs to aromatic rings which have given number of atoms, of which at least one is N, O or S, the remaining being carbon atoms, and which also optionally has methyl substituting group. Invention also relates to pharmaceutical composition, to application of compounds, as well as to method of obtaining formula I compounds.
EFFECT: obtaining novel biologically active compounds, possessing activity of receptor 5-HT2A antagonists.
9 cl, 25 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel substituted derivatives of 4-aminocyclohexanol of the general formula (I) being optionally as their physiologically acceptable salts and first of all physiologically compatible acids. In compound of the general formula (I) R1 and R2 mean independently of one another hydrogen atom (H) or (C1-C8)-alkyl that can be saturated or unsaturated but both R1 and R2 can't mean simultaneously H, or residues R1 and R form a ring in common and mean (CH2)3-6; R2 means unsubstituted phenyl or phenyl substituted with halogen atom that is added through saturated or unsaturated, branched or linear (C1-C4)-alkyl group; R4 means heteroaryl chosen from 5-membered heteroaryl wherein heteroatoms are chosen from nitrogen, oxygen or sulfur atoms and each of these atoms is condensed with benzene ring and means unsubstituted or monosubstituted (C1-C8)-alkyl; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7 wherein R6 represents H; R7 represents phenyl that can be unsubstituted or mono- either multi-substituted with halogen atoms. Also, invention relates to a method for synthesis of compounds of the formula (I) and a medicinal agent based on thereof. Synthesized compounds can be sued for preparing a medicinal agent designated for treatment of pain being first of all acute, visceral, neuropathic or chronic pain, and to a medicinal agent designated for treatment of diseases mediated by function of ORL1-receptor, for example, such as fear state, epilepsy, cardiovascular diseases.
EFFECT: improved method of synthesis, valuable medicinal properties of compounds and drug.
10 cl, 1 tbl, 21 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to arylsulfonyl derivatives of the formula (I): , wherein Ar means naphthyl or phenyl substituted optionally with halogen atom or (C1-C6)-alkoxy-group; R1 means (C1-C6)-alkyl; R2 means hydrogen atom or (C1-C6)-alkyl, or their pharmaceutically acceptable salts or solvates. Proposed compounds show affinity to HT6 receptors. Also, the claim describes pharmaceutical compositions comprising indicated compounds, their using as therapeutic agents and a method for their preparing. Compounds can be useful in treatment of some disturbances in the central nervous system (CNS).
EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.
12 cl, 1 tbl, 12 ex
FIELD: pharmaceutical chemistry, medicine.
SUBSTANCE: invention relates to new compounds of formula I ,
solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,
wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.
EFFECT: new antiarrhythmic drugs.
30 cl, 12 dwg, 34 ex
SUBSTANCE: invention relates to new compounds of formula (I) their pharmaceutically acceptable salts , where: m equals 0; p assumes values from 1 to 2; q equals 2; Ar is a possibly substituted phenyl, where the substitute is a halogen; R2 is ; each of n and r is independently equal to 1 or 2; X is -NR3 when n equals 2, or X is -CHNR4R5 when n equals 1 or 2, where each of R3, R4 and R5 is independently hydrogen or methyl. The invention also relates to a pharmaceutical composition based on these compounds having selective affinity to 5-HT receptors.
EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds which can be used in medicine to treat diseased conditions of the central nervous system and gastrointestinal tract disorders.
16 cl, 1 tbl, 4 ex
SUBSTANCE: invention relates to novel naphthalene derivatives of general formula I , as well as to their pharmaceutically acceptable salts, which can be used for treating and/or preventing diseases associated with H-3 receptor modulation. In formula I, R1 is selected from hydrogen, lower alkyl, phenyl, phenyl-lower alkyl and lower alkoxyalkyl; R2 is selected from hydrogen, lower alkyl, C3-C7-cycloalkyl, lower alkoxyalkyl or lower alkylsuphanylalkyl (all values of R1 and R2 are given in the formula of inventions); or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-7-member saturated or partially unsaturated heterocyclic ring which can contain one more heteroatom selected from nitrogen, oxygen and sulphur atoms, where the said heterocyclic ring can be unsubstituted or substituted with 1-2 groups, or can be condensed with an unsubstituted phenyl ring; A is selected from (values of R3-R7, R9, R10, X, m, n, t, p, q and s are given in the formula of invention). Invention also pertains to a pharmaceutical composition containing formula I compounds.
EFFECT: increased effectiveness of application.
30 cl, 2 tbl, 188 ex
SUBSTANCE: invention relates to novel 3-substituted 4-(phenyl-N-alkyl)piperazine compounds of formula (1) , where R1 represents OSO2CF3, OSO2CH3, SO2R3, COCF3 and COCH2CH3, R2 represents C1-C4 alkyl or allyl, R3 represents C1-C3 alkyl or CF3, as well as to their pharmaceutically acceptable salts. The disclosed compounds are capable of modulating dopamine neurotransmission.
EFFECT: invention discloses pharmaceutical compositions of compounds which are used for treating disorders of the central nervous system.
4 cl, 24 ex
SUBSTANCE: invention relates to a method of producing and aminophenol compound of formula (1) , where each of R1 and R2, which can be identical or different, are a hydrogen atom, C1-C6 alkyl group, which can be substituted with phenyl, or phenyl; R1 and R2 together with the neighbouring nitrogen atom can form a 5- or 6-member heterocyclic group, selected from piperidinyl and piperazinyl; the heterocyclic group can be substituted with one substitute selected from hydroxyl group, C1-C6 alkyl group and phenoxy group, which can have a C1-C6 alkoxy group, substituted with 1-3 halogen atoms. The method involves reacting a cyclohexanedione compound of formula (2) with a amine compound of formula (3) , where R1 and R2 assume values given above, in neutral or basic conditions.
EFFECT: wider range of use of the compound.
8 cl, 4 dwg, 13 ex
SUBSTANCE: in derivatives of 1,2-di(cyclo)substituted benzole of general formula I, their salts and hydrates , R10 is 5-10 member cycloalkyl, optionally substituted, or 5-10 member cycloalkenyl, optionally substituted, n=0, 1 or 2; XI is CH or nitrogen.
EFFECT: inhibiting activity with respect to cell adhesion or cell infiltration and application as therapeutic or preventive agent for inflammatory and autoimmune diseases, connected with adhesion and infiltration of leucocytes.
22 cl, 3 tbl, 118 ex
SUBSTANCE: invention pertains to quaternary ammonium salts, with formula (I) where R1 represents alkyl with a straight or branched chain, with between 1 and 4 carbon atoms, R2 represents methyl or ethyl and X represents a fluorine containing anion. The invention also relates to electrolytes, electrolytic solutions and electrochemical devices.
EFFECT: invention provides for electrochemical devices, used under high voltages, with high discharge capacity and capable of discharging by large current; the invention provides for electrolytic solutions, with high stability under voltage and high electrolytic conductance.
151 cl, 77 ex, 47 tbl, 10 dwg
FIELD: medicine; pharmacology.
SUBSTANCE: composition is intended for treatment or prevention of insulin resistance of susceptible warm-blooded animals, including humans, and contains selective modulator of estrogen receptor EM-652-HC1, taken in amount determined by therapeutic efficiency.
EFFECT: effective treatment of prevention of insulin resistance development for warm-blooded mammals.
5 cl, 20 ex, 12 tbl, 8 dwg
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel substituted derivatives of 5-amino-1-pentene-3-ol of the general formula (I)
as a free form or as their physiologically compatible salts possessing the analgesic effect. In general formula (I) each R1 and R2 means independently of one another (C1-C6)-alkyl that can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multi-substituted; or R1 and R2 form in common -(CH2)2-9-mono- or bicyclic ring; each R3 and R4 means independently of one another (C1-C6)-alkyl, or R3 and R4 form in common a ring and mean the group -CH2CH2NR22CH2CH2 wherein R22 represents (C1-C10)-alkyl; R5 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched, mono- or multi-substituted or unsubstituted, (C3-C9)-cycloalkyl that is saturated or means phenyl, heteroaryl that can be condensed with benzene ring and chosen from 5-membered heteroaryl with sulfur or oxygen atom as a heteroatom bound through saturated (C1-C3)-alkyl, phenyl bound through saturated (C1-C3)-alkyl-(C3-C10)-cycloalkyl wherein each among all these alkyl, phenyl, heteroaryl and cycloalkyl residues and independently of others can be unsubstituted or mono- or multi-substituted residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, groups -OR18, (C1-C3)-alkyl) that is saturated or branched or unbranched, mono- or multi-substituted halide, or unsubstituted and wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or unbranched; R6 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched and unsubstituted, phenyl or heteroaryl that is chosen from 5-membered heteroaryl with oxygen atom as a heteroatom wherein each of them is unsubstituted or mono- or multi-substituted as indicated above; R7 means H. Also, invention relates to a medicinal agent based on proposed compounds and to a method for their synthesis.
EFFECT: improved method of synthesis, valuable medicinal properties of compounds.
10 cl, 493 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to novel [(heterylonio)-methylcarbonyloxypoly(alkyleneoxy)]-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]propane trichlorides of the general formula: wherein: at X+ = Y+ means X+ means -N+R1R2R3 wherein R1 = R2 means hydrogen atom (H); R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e (total degree of oxypropylation) = 49; b + d + f (total degree of oxyethylation) = 9; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 10; at X+ means Y+ = Z+ means -N+R1R2R wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 9; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 10; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 0; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 0; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 0; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 0, and to a method for their synthesis. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]propane of the formula: wherein a + c + e = 55; b + d + f = 0-10 with monochloroacetic acid in the presence of acid catalysts, in organic solvent medium and with azeotropic removal of formed water and the following treatment at heating of the synthesized reaction productwith a mixture of morpholine and aliphatic amine in the molar ratio of reagents - hydroxyl derivative of propane: monochloroacetic acid : morpholine : aliphatic amine = 1:(3.0-3.2):(1.0-2.1):(1.0-2.1), respectively and wherein the total amount of morpholine and aliphatic amine is 3.0-3.2 mole. Novel compounds possess emulsifying properties for aqueous-bitumen and aqueous-mazut emulsions.
EFFECT: improved method of synthesis, valuable properties of compounds.
6 cl, 2 tbl, 8 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to novel 1,2,3-tris-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]-propane trichlorides of the general formula:
wherein at -X+ as -N+R1RR, R1 = R2 mean hydrogen atom (H), R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e (the general degree of oxypropylation) = 49,b + d + f (the general degree of oxyethylation) = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 55, b + d + f = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 90, b + d + f = 27; at -X+ as -N+R1R2R3, R1 = R2 means H, R3 means phenyl, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means phenyl, a + c + e = 90, b + d + f = 27; at -X+ as , a + c + e = 80, b + d + f = 24; at -X+ as , a + c + e = 90, b + d + f =27. Also, invention relates to a method for synthesis of these compounds. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]-propane of the formula:
wherein a + c + e = 49-90, b + d + f = 0-27 with monochloroacetic acid in the presence of acidic catalyst, in boiling organic solvent medium with azeotropic removal of water formed and the following treatment of synthesized reaction product in polar solvent medium at heating with amino-compounds of the formula: NR1R2R3 wherein R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, phenyl, or morpholine of the formula:
in the following mole ratios of reagents - propane hydroxyl derivative : monochloroacetic acid : amino-compound or morpholine = 1:(3.0-3.2):(3.0-3.2), respectively. New compounds show the bactericidal and fungicide activity and properties of demulsifying agents for petroleum emulsions.
EFFECT: improved method of synthesis, valuable properties of compounds.
7 cl, 3 tbl, 8 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: there is described a compound representing a new derivative of 3,5-seco-4-cholestane presented in the description, its salts, esters and ester salts as medicinal agents, application, particularly as neuroprotectors; besides there are described pharmaceutical compositions.
EFFECT: production of new derivatives of 3,5-seco-4-cholestane which can find application as neuroprotectors.
15 cl, 11 ex
FIELD: producing of caprolactam.
SUBSTANCE: device comprises two stages, circuits for circulation in the first and in the second stages, mixers for mixing cyclohexane, hydroxylamine sulfate, and ammonium, recycle of ammonium sulfur, pumps, heat exchanger, separating vessels, tanks for mixing and drying, pickups, and valves for control of pH of fluid by means of supplying ammonium.
EFFECT: enhanced efficiency.
1 cl, 2 dwg, 2 tbl, 2 ex