9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole hydrobromide eliciting property of serotonin 5-ht3-receptor antagonist

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel derivative of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole, namely its hydrobromide, eliciting properties of antagonist of serotonin 5-HT3-receptors that can be used in therapy of cytotoxic nausea and vomiting. New salt is low toxic and exceeds bemesetron by anti-serotonin activity that is a selective 5-HT3- antagonist.

EFFECT: improved and valuable medicinal properties of derivative.

2 cl, 2 ex

 

The invention relates to a derived N-imidazo[1,2-a]benzimidazole, namely hydrobromide 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]-benzimidazole of the formula I:

shows the properties of an antagonist of serotonin 5-HT3receptors.

One of the widely used medication to control nausea and vomiting caused by taking drugs, is metoclopramide (Konstantinov M.M. New supporting tools (antiemetic, bisphosphonates, colony-stimulating factors). Practical Oncology. 2002, Vol.3, No. 4, s-319; Register of medicines of Russia. Encyclopedia of drugs. Radar-Patent, 2004, s-542). The mechanism of action is selective blocker of dopamine D2and serotonin 5-HT3the receptors. (Waitling K. 5-HT3-receptor agonists and antagonists. Neurotransmissions, RBI, 1989, vol. V, No. 3, p.1-5).

However, the drug is often accompanied by severe side effects such as drowsiness, headache, dizziness, depression and extrapyramidal disorders, the latter arise as with long-term use, and with a single admission (children and young people). In addition, you may experience agranulocytosis (Egerer G., Hegenbart U., Salwender H.J. et al. Treatment of chemotherapy-induced emesis. Karthaus M., Ganser, A. (eds): Supportive care in cancer patients. The Recent developments. Antibiot Chemother. Basel, Karger, 2000, vol.50, p.171-18; On The Main Page. Medications Russia. M: Attraversare, 2004, s-1321).

For cytotoxic therapy nausea and vomiting apply selective blockers of serotonin 5-HT3receptors, which are currently considered the drugs of choice (Egerer G., Hegenbart U., Salwender H.J. et al. Treatment of chemotherapy-induced emesis. Karthaus M., Ganser, A. (eds): Supportive care in cancer patients. The Recent developments. Antibiot Chemother. Basel, Karger, 2000, vol.50, pp.171-183; Konstantinov M.M. New supporting tools (antiemetic, bisphosphonates, colony-stimulating factors. Practical Oncology. Vol.3, No. 4, 2002. s-319). One of these drugs is Betaseron (MDL 72222) (Cheng H., Larsen D., Ragner J. et al. Disposition of 8-methyl-8-azabicyclo(3,2,1)octan-3-yl 3,5-dichlorobenzoate, a potent 5-HT antagonist, and two metabolites in dogs and monkeys, J. Pharm.Sci., Vol.81, 1992, pp.345-347; Logue J., Wilkinson P., Haegele K, et al. A single-dose-finding study of the antiemetic effect and associated plasma levels of MDL 72222 in patients receiving cisplatin. Cancer Chemother. PharmacoL, Vol.27, No. 6, 1991, pp.472-476).

The major adverse effects when using drugs of this class is headache, constipation or diarrhea, drowsiness (Rosen R., Irani M. Evaluation of 5-HT3antagonists and nausea and vomiting outcomes in cancer patients. ASHP Annual Meeting, Vol.57, 2000, p.40; Hesketh P. Comparative review of 5-HT3receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Investigation, Vol.18, No. 2, 2000, pp.163-173). In addition, one of the problems is the refractoriness of cytotoxic nausea and vomiting to well-known 5-HT3antagonista number of patients (Konstantinov M.M. New support tools (antiemetic, bisphosphonates, colony-stimulating factors). Practical Oncology. Vol.3, No. 4, 2002. s-319).

Described dihydrochloride 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole, exhibiting hypotensive and sedative properties (Simonov A.M., Belous A., Anisimov, V.A., Ivanov SV, Chem. Pharm. journal, 1969, Vol.3, No.1, p.7-10).

Known dinitrate treatment 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]-benzimidazole, having antisecretory and antiulcer aktivnosti (Kovalev, GV, Spasov AA, Anisimov, VA and other Pat. No. 2058142 (RF), class a 61 K 31/415; bull. Fig., 1996, No. 11), as well as hypotensive and anti-inflammatory action (Simonov M., Kovalev, GV, Anisimov, VA and others, Ed. mon. No. 566588 (USSR), M. CL2. A 61 K 31/475; bull. Fig., 1977, No. 28; Kovalev, GV, Anisimov, V.A. Simonov, A.M., and others, Khim.-Pharm. journal, 1979, Vol.13, No. 8, p.57-62).

The closest structure among derivatives N-imidazo[1,2-a]-benzimidazole is dihydrobromide 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole with anti-hypertensive and anti-inflammatory activity (Simonov M., Kovalev, GV, Anisimov, VA and others, Ed. mon. No. 566588 (USSR), M. CL2. A 61 K 31/475; bull. Fig., 1977, No. 28; Kovalev, GV, Anisimov, V.A. Simonov, A.M., and others, Khim.-Pharm. journal, 1979, Vol.13, No. 8, p.57-62).

The technical result of the invention is a new property (antiserotonin the TV) in a series of salts of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole.

The technical result of the invention is achieved by a compound of formula I. the Synthesis of compound I is in the cyclization bromide 2-amino-1-diethylaminoethyl-3-phenacylbromides resulting from the interaction of 2-amino-1-diethylaminoethylmethacrylate with penacerrada in the environment of acetone or acetonitrile boiling water and direct selection of the desired substances from the reaction medium.

Below are examples of methods of synthesis and studies of biological activity of the proposed connection.

Example 1. The hydrobromide 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole (I). To the warm solution of 79.6 g (0.3 mol) of 2-amino-1-diethylaminoethylmethacrylate in 1 l of acetone was added with stirring a solution of 61.7 g (0.31 mol) of pencilvania in 200 ml of acetone and continue stirring until the precipitate discarded. Leave the mixture at room temperature until the next day, the precipitation bromide 2-amino-1-diethylaminoethyl-3-phenacylbromides filtered off, washed with acetone and dried at 95-100°C. Exit 127, 6 g (98.7 per cent). TPL 186-187°C. the Compound is administered in the cyclization without further purification.

In a round bottom 1-liter flask equipped with a fridge and a stirrer, placed 108 g (0.25 mol) of the obtained bromide and 600-650 ml of water. The mixture is heated under stirring until a key is placed and boil until complete reaction (1.5-2 hours), what are judged by the disappearance of the spot of the initial compounds on TLC. When this sediment source bromide dissolved and formed a yellowish solution. It is cooled and the precipitate end hydrobromide is filtered off, thoroughly drained, washed with ice water and acetone. Dried at 95-105°C to constant weight. The output of salt the 98.9 101.0 g (96-98%). After recrystallization from aqueous alcohol TPL 203-204°C. Found, %: C 61,24; N 6,02; VG 19,00; N 13,76. C21H24N4·NVG. Calculated, %: C 61,15; N 6,11; Br 19,15; N 13,59. UV-spectrum (95%ethanol), λmaxnm: 216±2, 233-234 (shoulder), 276±2. IR spectrum (liquid paraffin), νcm-1: 1665 (C=N+H, 3130-3600 N+N). Range PMR base (CDCl3), δ, ppm: 0,97 (6N, t, 2CH3), 2,52-by 2.73 (4H, K, 2CH2CH3), 2,90 totaling 3.04 (2H, t,CH2N(CH2CH3)2), 4,22 is 4.36 (2H, t, NCH2), 7,12-7,93 (10 H, m, fragrance. protons).

Example 2. The study antiserotonin activity and toxicity. Determination of antagonistic activity of bromide I relative to 5-HT3the subtype of serotonin receptors was performed on isolated atropinization the Atria of Guinea pigs according to the method described in H.Nishio et al. (Nishio H., Fujii, A., Nakata, Y., Behav. Brain Res., 1996, Vol.73, No. 1-2, p.301-304).

Isolated Atria of the Guinea pig was placed in Krebs solution and thermostatically at 32°PR is constant oxygenation. Before the introduction of the agonist of serotonin receptors were injected atropine sulphate at a dose of 10-6M as agonist 5-HT3receptors used hydrochloride serotonin (ICN Biomedicals, USA) at a dose of 10-6M Comparators were: non-selective blocker - metoclopramide (Polpharma, Poland) and selective blocker of serotonin 5-HT3receptor - Betaseron (MDL-72222) (ICN Biomedicals, USA). Registration pharmacological response was made isotonic transducer and recorder of the firm UGO BASILE, Italy). The time of incubation of the analyte and reference product was 2 minutes the Amount of 5-HT3the blocking activity was assessed by the change in the severity of positive chronotropic effect induced by serotonin.

For the studied compounds and Betaseron were experimentally determined values pA2(the negative logarithm of the concentration of antagonist, the infusion of which the agonist in double concentration has an effect equal to that with the introduction of a single concentration of agonist, but without the introduction of the antagonist) (Arunlakshana, O., H.O. Schild // Brit.J.PharmacoL, 1956, Vol.14, No.1, P.48-58).

The results were processed statistically using one-way ANOVA.

Acute toxicity of the compounds was studied on white outbred mice-males masses is th 18-22 g intraperitoneal injection. The calculation of LD50produced according to the method of Prozorovsky (Prozorovsky V.B. have been et al., Pharmacol. and toxicol, 1978, No. 4, s-502).

therapeutic index for the analyte of interest and the comparison drug was calculated as the ratio LD50to the concentration of the substance corresponding to the value of RA2.

The study of the effects of substances on the frequency of contractions of isolated atropinization the Atria of Guinea pigs at a concentration of 10-6M discovered that the test substance inhibits the positive chronotropic response to serotonin 66.7±5.3 per cent, while metoclopramide and Betaseron - 35.2±9,5% and 38.9±8.2%, respectively (data is significant in relation to control (P≤0,05).

Thus, the level of antiserotonin activity of compound I exceeds such drugs comparison of metoclopramide and Betaseron - practically 2 times with the introduction of micromolar concentrations.

During the experimental determination of RA2for compounds I and Betaseron value amounted to 9,89 and being 9.61, respectively. When comparing these values in pA2compound I is also 2 times higher than in antiserotonin activity of selective 5-HT3-blocker - Betaseron.

According to the results of studies of acute toxicity indicator LD50intraperitoneal injection for I hydrobromide SOS the start-UPS amounted to 115.5 mg/kg, while the same indicator for Betaseron (MDL-72222) is of 32.0 mg/kg

The index of relative safety, therapeutic index was 8,96 for compound I and 1.3 for Betaseron.

Thus, pharmacological research hydrobromide 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole (I) showed that the studied substance has antiserotonin activity.

When comparing this connection used in experimental and clinical practice drugs metoclopramide and Betaseron was found that compound I at a dose of 1 μm exceeds the Comparators about 2 times. Largest index of antagonistic activity of RA2test substance 2 times a selective antagonist of serotonin 5-HT3-receptors Betaseron. In addition, the bromide I 3.6 times less toxic than Betaseron, and the relative security value toxicity/activity) for this connection in 7 times higher than that in Betaseron.

Studied substance I may be applied as a medicinal product for the treatment of cytotoxic nausea and vomiting.

The hydrobromide 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole of the formula I:

shows the properties of the antagonist with whom rotodynamic 5-HT 3-receptors.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to new compounds of the formula (I) wherein R1 and R2 can be similar or different and represent independently (C1-C6)-alkyl that are selective inhibitors of enzyme phosphodiesterase, and to their pharmaceutically acceptable salts or stereoisomers. Also, invention involves a method for preparing the preferable compound, i. e. 5-[[2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulfonyl)phenyl]]-1-methyl-3-n-propyl-7,6-dihydro-1H-pyrazolo[4,3-d]pyrimidine-7-one. Also, invention proposes new intermediate compounds used in method for synthesis of this compound. Compounds of the formula (I) show very high effectiveness in treatment of diseases associated with impotence, such as the male erectile sterility but they exhibit such features as prolonged therapeutic effectiveness and lower toxicity. Also, invention relates to a pharmaceutical composition used in treatment of impotence and using compound of the formula (I) in preparing the medicinal preparation designated for treatment of diseases associated with impotence.

EFFECT: valuable medicinal properties of compound.

8 cl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

10 cl, 9 tbl, 11 ex

FIELD: organic chemistry, medicine.

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EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

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EFFECT: valuable medicinal properties of compounds and composition.

15 cl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

11 cl, 2 tbl, 27 ex

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EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

7 cl, 15 ex

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SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

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EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, herbicides.

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EFFECT: improved preparing method, valuable properties of compounds and agents.

5 cl, 28 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: medicine, pharmacy.

SUBSTANCE: medicinal formulation possessing an anti-vomiting effect consists of core and envelope dissolving in stomach. Core comprises the following components, wt.-%: domperidone, 2.0-40.0; starch, 7.0-18.5; sodium dodecyl sulfate, 0.1-0.3; polyvinylpyrrolidone, 1.5-4.0; calcium stearate, 0.5-1.2; aerosil, 1.0-3.0; lactose, 49.9-71.0. Envelope comprises the following components, wt.-%: hydroxypropylmethylcellulose, 50.0-70.0; Twin-80, 15.0-25.0, and titanium dioxide, 15.0-25.0. Also, invention describes a method for preparing the medicinal formulation by wet granulation followed by tableting and applying a coating from an aqueous suspension. Deviation of separate tablets by mass is 4.5-5.5%. Tablets possess sufficient strength for qualitative applying the envelope. Decomposition time of tablets is 6-7 min. From 97.8% to 98.4% of domperidone is released from tablet to solution for 45 min.

EFFECT: improved and valuable pharmaceutical properties of medicinal formulation.

3 cl, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a composition comprising as active components pyridoxine hydrochloride and doxylamine succinate and a disintegrating agent that provide the following dissolving pattern: 20-90% of the total amount of each component among pyridoxine hydrochloride and doxylamine succinate are dissolved in 5-120 min. The composition is made preferably as a tablet with an enterosoluble envelope. The tablet has a core comprising pyridoxine hydrochloride and doxylamine succinate, and inactive excipients also. The composition is used in treatment of nausea, vomiting being especially in pregnancy. The composition provides rapid and simultaneous release of synergetic pair of indicated active components.

EFFECT: improved and valuable properties of composition.

24 cl, 2 dwg, 9 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves odorizing anti-emetics given to a patient and determining pupil area in the left eye. The area reducing more than by 18% when compared to the initial one, sickness and vomiting is to be predicted.

EFFECT: high accuracy of prognosis.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

FIELD: stomatology.

SUBSTANCE: patient rinses his/her oral cavity with 10-12% sodium chloride solution at 25-40°C for 20-25 min, after which, 10-15 min later, denture is placed into oral cavity.

EFFECT: achieved prolonged reduction in emitting reflex activity.

3 ex

The invention relates to the field of medicine and relates to means for reducing the toxicity of anticancer drugs, characterized in that the pharmacologically active agent used benzamid in doses ranging from 5 to 100 mg/kg

The invention relates to pharmaceutical and veterinary use, namely, to pharmaceutical compositions containing ondansetron, metacin and benzamid

The invention relates to the field of medicine and veterinary medicine and relates to pharmaceutical compositions containing ondansetron and benzamid in amount from 1:4 to 1:200

The invention relates to medicine, namely to surgical gastroenterology, and can be used as a means to prevent vomiting after laparoscopic cholecystectomies

The invention relates to medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to the improved thrombopoietin TPO) mimetic representing 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-yliden]hydrazine]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine). Also, invention relates to a pharmaceutical composition based on indicated salt of the compound, method for treatment of thrombocytopenia in mammal, method for enhancing platelets producing in mammal and methods for preparing indicated pharmaceutical composition and indicated salt of the compound. Invention provides the enhanced solubility of proposed salt as compared with free acid that results to alleviation in preparing the pharmaceutical composition and enhancing biological availability in using indicated salt as agonist of TPO receptors for enhancing platelets producing and in treatment of thrombocytopenia also.

EFFECT: improved and valuable medicinal properties of acid.

19 cl, 2 tbl, 5 ex

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