The present invention relates to novel antiviral component, pharmaceutical composition, antiviral medicament, method for prophylaxis and treatment of viral diseases, particularly caused by hepatitis C virus (HCV).
Virus infections may cause a great number of diseases that create a serious threat for health and existence of mankind For the last 20 years no less than 30 essentially new infectious agents have been discovered such as: HIV, viral hepatitises, acute and long-lasting diarrhea, hemorrhagic fever (Ebola, Venezuelan, Brazilian, Rift valleys) [a) Lednicky J. A., Rayner J. O. Uncommon respiratory pathogens. Curr. Opin. Pulm. Med. 2006, 12(3), 235-239. b) Hayden F. G. Respiratory viral threats. Curr. Opin. Infect. Dis. 2006, 19(2), 169-178]. In particular, special anxiety is caused by the risk of infection by so named avian influenza. [a) Liu J. P. Avian influenza—a pandemic waiting to happen? J. Microbiol. Immunol. Infect. 2006, 39(1), 4-10. b) Henter J. I.; Chow C. B.; Leung C. W, Lau Y. L. Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet. 2006 367(9513), 870-873. Review]. According to statistical data 60-65% of epidemic infections have viral ethiology. Because of the complexity of interaction in triad “virus—host's organism—drug”, most of modern antiviral drugs display side effects in the course of therapy and form resistant virus strains [Jain R., Clark N. M., Diaz-Linares M., Grim S. A. Limitations of current antiretroviral agents and opportunities for development. Curr. Pharm. Des. 2006, 12(9), 1065-1074.]. At present, the number of antiviral drugs that could be used in clinical practice is extremely limited—only 43 low molecular weight substances [http://integrity.prous.com/integrity], that is far from covering requirements of prophylaxis and treatment of virus diseases. Moreover, there are a lot of virus infections causing diseases for treatment of which there are no chematherapeutic agents. This is particularly true, for example, for the diseases caused by viruses of papilloma, adenoviruses, herpes-6, variola, syndrome SARS, hemorrhagic fevers, fever of the Western Nile, avian influenza and so on [De Clercq E. Recent highlights in the development of new antiviral drugs. Curr Opin Microbiol. 2005, 8(5), 552-560].
Therefore, the development of novel antiviral medicaments, particularly exhibiting novel mechanism of antiviral action, high activity and low toxicity are of great importance now.
International applications WO 2009039246 A2 and WO 2009039248 A2 were published, in which novel antiviral active ingredients, which are Clemizole I and its analogs, for example, benzimidazole II, intended for prophylaxis and treatment of viral diseases caused by hepatitis C virus (HCV) were described.
However, many substituted indoles exhibiting activity towards HCV have not been known so far.
So, the research for highly effective antiviral medicaments is still one of the main directions in the development of novel pharmacological remedies for treatment of wide and various types of viral infections.
In the context of the invention, the terms are generally defined as follows:
The subject of the present invention is novel antiviral component, which is substituted indole of the general formula 1, or a pharmaceutically acceptable salt thereof,
wherein:
wherein R1a is methyl, ethoxycarbonyl, phenyl, nitro group, R4a is hydrogen, methyl, C2-C3 alkyl optionally substituted with N-benzylamine;
wherein R11 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;
The preferred antiviral active component is substituted amide of 1-[(1H-indol-2-yl)methyl]piperidine-4-carboxylic acid of the general formula 1.3.1 or substituted amide of 1-[(1H-indol-2-yl)methyl]piperidine-3-carboxylic acid of the general formula 1.3.2, or a pharmaceutically acceptable salt thereof,
wherein
The more preferred antiviral active component is the antiviral active component representing substituted amide of 1-[(1H-indol-2-yl)methyl]piperidine-4-carboxylic acid of the general formula 1.3.1.1 or a pharmaceutically acceptable salt thereof,
wherein:
The preferred antiviral active component is an antiviral component of general formula 1.1, active towards hepatitis C virus (HCV), or a pharmaceutically acceptable salt thereof,
wherein:
The more preferred antiviral active component is the antiviral active component exhibiting antiviral activity towards HCV, representing substituted indole of the general formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, or pharmaceutically acceptable salt thereof.
The subject of the present invention is also a pharmaceutical composition exhibiting antiviral activity and comprising pharmaceutically effective amount of antiviral active component representing at least one substituted indole of general formula 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1 or pharmaceutically acceptable salts thereof.
The more preferable composition is the pharmaceutical composition exhibiting antiviral activity towards hepatitis C virus (HCV) comprising as an active component at least one substituted indole of general formula 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, or a pharmaceutically acceptable salt thereof.
Pharmaceutical compositions may include pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients mean diluents, auxiliary agents and/or carriers employing in the sphere of pharmaceutics. According to the invention the pharmaceutical composition in addition to substituted indole of general formula 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, or pharmaceutically acceptable salt thereof, may include other active components, provided that they do not give rise to undesirable side-effects.
According to the present invention, if it is necessary to use the pharmaceutical composition in clinical practice it can be mixed up with various traditional pharmaceutical carries.
According to the present invention the carriers used in pharmaceutical compositions represent carriers which are applied in the sphere of pharmaceutics for preparation of commonly used forms including: binding agents, greasing agents, disintegrators, solvents, diluents, stabilizers, suspending agents, colorless agents, taste flavors are used for peroral forms; antiseptic agents, solubilizers, stabilizers are used in the forms for injections; base materials, diluents, greasing agents, antiseptic agents are used in local forms.
The subject of the present invention is also a method for preparation of pharmaceutical composition. The object in view is achieved by mixing, at least one antiviral active component representing substituted indole of general formula 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable excipients, an inert filler and/or solvent.
The subject of the present invention is also a medicament intended for treatment of viral diseases comprising novel antiviral component which is at least one substituted indole of the general formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1 or its pharmaceutically acceptable salt, or novel pharmaceutical composition including that active component in the form of tablets, sheaths or injections placed in pharmaceutically acceptable packing.
According to the invention the more preferable medicament is the medicament intended for treatment diseases caused by HCV viruses.
Medicaments could be administered perorally or parenterally, for example, intravenously, subcutaneously, intraperitoneally or locally. The clinical dosage of the pharmaceutical composition or medicament comprising antiviral active component of general formuls 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, could be corrected depending on: therapeutic efficiency and bioavailability of the active ingredients in organism, rate of their exchange and deducing from organism, and also depending on the age, sex and the severity of the patient's symptoms; the daily dosage for adults falls within the range of about 10 to about 500 mg of the active ingredient, preferably of about 50 to about 300 mg. Therefore, according to the present invention in the process of preparation of a medicament from the pharmaceutical composition as units of dosage it is necessary to keep in mind the above effective dosage, so that each unit of dosage should contain of about 10 to about 500 mg of active component of general formula 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, preferably 50˜300 mg. In accordance with the recommendation of physician or pharmacist the above dosage can be taken several times during the definite time intervals (preferably—from one to six times).
The subject of the present invention is also a therapeutic cocktail for prophylaxis and treatment of viral diseases, among them diseases caused by hepatitis C viruses, including novel active component or novel pharmaceutical composition comprising, at least one substituted indole of general formula 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, or a pharmaceutically acceptable salt thereof.
A therapeutic cocktail for prophylaxis and treatment of hepatitis C along with the medicament disclosed in the invention, may include: inosine-5-monophosphate dehydrogenase inhibitors, for example, Ribavirin (licensed) and Ribamidil; inhibitors of hepatitis C NS3 protease, for example, Telaprevir, Ciluprevir and SCH-503034; inhibitors of RNA-polymerase NS5B, for example, XTL-2125; alpha-glucosidase inhibitors, for example, aminocarbohydrate Selgozivir; and also TLR-receptor agonists, hepatoprotectors, cyclosporines, various proteins (for example, interferons), antibodies, vaccines and so on.
The subject of the present invention is also method for prophylaxis and treatmemt of viral diseases at animals and humans.
According to the present invention a method for prophylaxis and treatment of viral diseases at humans and animals, among them diseases caused by hepatitis C viruses, consists in introduction to warm-blooded animal or human novel medicament, or novel pharmaceutical composition or novel therapeutic cocktail, comprising novel antiviral active component of the general formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1 or its pharmaceutically acceptable salt in effective amount.
The subject of the present invention is also the unknown before 2-(8-isopropyl-1,2,3a,4,5,6-hexahydro-3H-pyrazino[3,2,1-Jk]carbazol-3-yl)acetamide or hydrochloride salt of formula 1.2(1).HCl
The subject of the present invention is the unknown before a substituted amide of general formula 1.3.1 or a substituted amide of general formula 1.3.2, or a pharmaceutically acceptable salt thereof,
wherein:
The subject of the present invention are the unknown before substitute amide of general formula 1.3.1.1 or a substituted amide of general formula 1.3.2.1, or a pharmaceutically acceptable salt thereof,
wherein:
The more preferable substituted amides are: {1-[1-(4-chlorobenzyl)-1H-indol-2-ylmethyl]-piperidin-4-yl}-(4-propylpiperazin-1-yl)-methanone 1.3.1.1(13), {1-[1-(4-chlorobenzyl)-1H-indol-2-ylmethyl]-piperidin-3-yl}-(4-propylpiperazin-1-yl)-methanone 1.3.2.1(13), [1-(1-methyl-1H-indol-2-ylmethyl)-piperidin-4-yl]-(4-propylpiperazin-1-yl)-methanone 1.3.1.1(14), [1-(1-methyl-1H-indol-2-ylmethyl)-piperidin-3-yl]-(4-propylpiperazin-1-yl)-methanone 1.3.2.1(14) and hydrochlorides thereof.
The subject of the present invention is also a method for preparation of substituted amides of 1-(1H-indol-2-ylmethyl)-piperidine-carboxylic acids of the general formulas 1.3.1, 1.3.2 and pharmaceutically acceptable salts thereof which consists in interaction of substituted 1-(1H-indol-2-ylmethyl)-piperidine-carboxylic acids of the general formulas 2.1, 2.2 with amines 3. The best results were obtained if the reaction was carried out in the presence of 1,1′-carbonyldiimidazole. Pharmaceutically acceptable salts of amides 1.3.1, 1.3.2 were prepared by interaction of bases 1.3.1, 1.3.2 with the corresponding acids in the medium of suitable organic solvent.
wherein:
The subject of the present invention is also a method for preparation of 2-(8-isopropyl-1,2,3a,4,5,6-hexahydro-3H-pyrazino[3,2,1-Jk]carbazol-3-yl)acetamide hydrochloride of formula 1.2(1).HCl by hydrogenation of 9-[2-(dibenzylamino)ethyl]-6-isopropyl-3,4-dihydro-2H-carbazol-1(9H)-one in the presence of 10% Pd/C with subsequent alkylation of obtained 2-(8-isopropyl-1,2,3a,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazole by chloroacetamide and transformation of the prepared base into its hydrochloride according to the following scheme:
The examples given below illustrate but not limit the scope of the invention.
Determination of antiviral activity of compounds of the general formula 1 towards hepatitis C viruses.
Determination of antiviral activity of compounds of the general formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1 towards HCV was carried out on Huh7 cell culture. Immune in vitro (ELISA—enzyme-linked immunosorbent assay) test ELISA towards HCV virus cor-antigen was used. By means of this test inhibition effectiveness of antigen production (and, consequently, virus replication) by tested compounds in cells infected by JFH-1 virus was measured. Used in this experiment Huh7 cell culture having been infected with HCV virus is capable to support full range of viral replication.
Recombinant JFH-1 HCV virus used in the experiment was prepared by means of transfection of Huh7 cells by RNA JFH-1, prepared by transcription in vitro. JFH-1 DNA [Wakita, T. u ∂p. Production of Infectious Hepatitis C Virus in Tissue Culture from a Cloned Viral Genome. Nature Medicine 2005, 11:791-796.]) used as DNA matrix for transcription (NCBI, catalogue number AB047639, was synthesized chemically.
Huh7 cells were sowed in 96-well plates (3.0×103 cells in every well) Huh-7 medium (50 μl per every well). 9 solutions of every tested compound in Huh-7 medium in the range of concentrations of 0.09-200 μM were prepared. In 4 h after cell sowing the initial solution was removed by aspiration, after that 50 μl of tested compound solution and 50 μl of JFH-1 HCV were added to every well. As a result, the final concentrations of the tested compounds were in the range of 0.045-100 μM. If required the step of infection was carried out in 24 h after addition of tested compounds. After incubation for 16 h viral medium was removed by aspiration, and the tested compounds were added to the cultures in initial concentration to final value of 200 μl. The cells and tested compounds were incubated additionally for 4 days at 37° C. in the atmosphere of air containing 5% CO2. After the removal of nutrient solution the cells were fixed by addition of acetone/methanol (1:1) mixture in amount of 250 μl/well for 1 minute, washed three times with Phosphate Buffer (PBS buffer and then they were blocked by 10% FBS-PBS solution (150 μl/well)) for 1 h at room temperature. Each well was washed three times with PBS solution, incubated with mouse monoclonal antibodies to HCV cor-antigen (Affinity BioReagents, Catalogue: MA1-080), dissolved in FBS-PBS buffer (100 μl/well, prepared from the initial concentrate, diluted in the ratio 1:500 in 10% FBS-PBS), for 2 h at 37° C. Each well was washed three times with PBS solution, incubated with antibodies specific to mouse immunoglobulins, conjugated with horseradish peroxidase (HRP, 100 mkl/well of solution prepared from the initial concentrate, diluted in ratio 1:2500 in 10% FBS-PBS) for 1 h at 37° C. Each well was washed three times with PBS solution, then treated with OPD solution in amount of 100 μl/well (prepared by dilution of one OPD tablet in
The Table shows IC50 values of substituted indoles of the general formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, reflecting their ability to inhibit hepatitis C virus.
Substituted indoles of the general formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 exhibit high activity towards HCV (Table). As a rule, they are more active, then the known agents I and II [WO 2009039246 A2, WO 2009039248 A2]. For example, compounds 1.3.1.1(2) and 1.3.1.1(13) have IC50=0.3 μM, and compounds 1.1(8), 1.3.1(2) and 1.3.1.1(7) have IC50=0.4 μM.
2-(8-Isopropyl-1,2,3a,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazol-3-yl)-acetamide hydrochloride 1.2(1).HCl. Solution of 9-[2-(dibenzylamino)ethyl]-6-isopropyl-3,4-dihydro-2H-carbazol-1(9H)-one (8.45 g, 18.8 mmol) in methanol (80 ml) was hydrogenated with 10% Pd/C (0.5 g) in autoclave at 30 atm for 24 h at 70° C. The solution was filtered through celit and evaporated in vacuo. The residue of obtained 2-(8-isopropyl-1,2,3a,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazole was boiled with chloroacetamide (1.93 g, 20.6 mmol) and K2CO3 (3.88 g) in acetonitrile (50 ml) for 12 h. The solvent was distilled in vacuo, the residue was treated with water and extracted with CH2Cl2. Extract was dried over Na2SO4, evaporated and the product was recrystallized from ethanol. It gave 3.27 g (56%) 2-(8-isopropyl-1,2,3a,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazol-3-yl)-acetamide 1.2(1). LCMS (M+H)+ 312. 1H NMR (CDCl3, 400 MHz) δ 7.34 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.10 (dd, J1=8.4 Hz, J2=1.2 Hz, 1H), 7.02 (br. s, 1H), 5.50 (br.s, 1H), 4.18 (dd, J1=11.6 Hz, J2=3.6 Hz, 1H), 3.84 (dt, J1=11.6 Hz, J2=4.8 Hz, 1H), 3.59 (m, 1H), 3.53 (d, J=12.8 Hz, 1H), 3.23 (dd, J1=12.4 Hz, J2=4.8 Hz, 1H), 3.06 (m, 3H), 2.82 (dd, J1=11.6 Hz, J2=6.4 Hz, 1H), 2.70 (m, 1H), 2.22 (m, 2H), 1.86 (m, 1H), 1.53 (m, 1H), 1.32 (d, J=6.8 Hz, 6H). 2-(8-Isopropyl-1,2,3a,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazol-3-yl)-acetamide hydrochloride 1.2(1).HCl was precipitated by addition of 5% excess of 3N HCl solution in dioxane to solution of base 1.2(1) in CH2Cl2. 1H NMR (DMSO-d6, 400 MHz) δ 10.89 (br. s, 1H), 8.16 (br. s, 1H), 7.75 (br. s, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 4.77 (br. m, 1H), 4.46 (d, J=6.4 Hz, 1H), 4.25 (br. m, 1H), 3.95 (br. m, 4H), 2.97 (d, J=6.8 Hz, 1H), 2.73 (br. d, J=15.6 Hz, 1H), 2.58 (br. m, 1H), 2.35 (br. m, 1H), 2.20 (br. m, 1H), 1.78 (br. m, 2H), 1.24 (d, J=6.8 Hz, 6H).
Amides of 1-(1H-indol-2-ylmethyl)piperidine-carboxylic acids of the general formulas 1.3.1, 1.3.2 (general method). 1,1′-Carbonyldiimidazole (1.95 g, 12 mmol) was added to suspension of acid 6 (10 mmol) in dry acetonitrile (45 ml). The mixture was stirred for 3 h at 70° C. (TLC control), cooled to room temperature, then the corresponding piperazine (12 mmol) was added, and stirring was continued at 70° C. for 12 h (LCMS control). After the reaction was completed the mixture was poured into water, precipitated solid was filtered off, washed with water several times and dried in vacuo. It gave amides 1.3.1, 1.3.2. Dihydrochlorides of amides 1.3.1, 1.3.2 were prepared by addition of 5% excess of 3 N HCl solution in dioxane to solution of amides in ether (5 g in 500 ml).
1-Methyl-2-({4-[(4-propylpiperazin-1-yl)carbonyl]piperidin-1-yl}methyl)-1H-indole dihydrochloride 1.3.1.1(14)*2HCl. Yield is 28%. LCMS (M+H)+ 383. 1H NMR (DMSO-d6, 400 MHz) δ 11.29 (br. s, 1H), 10.80 (br. s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.23 (m, 1H), 7.09 (m, 1H), 6.80 (s, 1H), 4.55 (br. s, 2H), 4.39 (br. m, 1H), 4.11 (br. m, 1H), 3.85 (s, 3H), 3.59 (br. m, 1H), 3.51 (br. m, 2H), 3.43 (br. m, 2H), 3.12 (m, 1H), 2.98 (br. m, 5H), 2.86 (br. m, 2H), 2.73 (s, 3H), 1.96 (br. m, 2H), 1.82 (br. m, 2H), 1.72 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).
1-Methyl-2-({4-[(4-methylpiperazin-1-yl)carbonyl]piperidin-1-yl}methyl)-1H-indole 1.3.1.1(15). Yield is 56%. LCMS (M+H)+ 355. 1H NMR (DMSO-d6, 400 MHz) δ 11.41 (br. s, 1H), 10.93 (br. s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.23 (m, 1H), 7.08 (m, 1H), 6.81 (s, 1H), 4.54 (br. s, 2H), 4.40 (br. m, 1H), 4.12 (br. m, 1H), 3.85 (s, 3H), 3.50 (br. m, 5H), 3.00 (br. m, 4H), 2.87 (br. m, 2H), 2.73 (s, 3H), 1.98 (br. m, 2H), 1.82 (br. m, 2H).
1-Methyl-2-({3-[(4-methylpiperazin-1-yl)carbonyl]piperidin-1-yl}methyl)-1H-indole dihydrochloride 1.3.2.1(1). Yield is 46%. LCMS (M+H)+ 355. 1H NMR (DMSO-d6, 400 MHz) δ 11.28 (br. s, 1H), 11.14 (br. s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.22 (m, 1H), 7.07 (m, 1H), 6.83 (br. m, 1H), 4.57 (br. s, 2H), 4.37 (br. m, 1H), 4.07 (br. m, 1H), 3.87 (s, 3H), 3.55 (br. m, 1H), 3.42 (br. m, 4H), 3.14 (br. m, 2H), 3.02 (br. m, 3H), 2.89 (br. m, 1H), 2.72 (br. m, 3H), 1.98 (br. m, 1H), 1.86 (br. m, 2H), 1.44 (br. m, 1H).
1-Methyl-2-({3-[(4-propylpiperazin-1-yl)carbonyl]piperidin-1-ylmethyl)-1H-indole dihydrochloride 1.3.2.1(2). Yield is 47%. LCMS (M+H)+ 383. 1H NMR (DMSO-d6, 400 MHz) δ 11.19 (br. m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.22 (m, 1H), 7.07 (m, 1H), 6.83 (br. m, 1H), 4.56 (br. s, 2H), 4.37 (m, 1H), 4.05 (m, 1H), 3.87 (s, 3H), 3.61 (m, 1H), 3.44 (br. m, 5H), 3.14 (br. m, 2H), 2.98 (br. m, 4H), 2.86 (br. m, 1H), 1.98 (br. m, 1H), 1.86 (br. m, 2H), 1.70 (br. m, 2H), 1.44 (br. m, 1H), 0.89 (br. m, 3H).
1-(4-chlorobenzyl)-2-({3-[(4-methylpiperazin-1-yl)carbonyl]piperidin-1-yl}methyl)-1H-indole dihydrochloride 1.3.2.1(12). Yield is 79%. LCMS (M+H)+ 465, 467. 1H NMR (DMSO-d6, 400 MHz) δ 11.07 (br. m, 2H), 7.63 (d, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.17 (m, 1H), 7.09 (m, 1H), 6.98 (br. m, 1H), 6.93 (d, J=8.0 Hz, 2H), 5.69 (br. s, 2H), 4.50 (br. s, 2H), 4.38 (br. m, 1H), 4.07 (br. m, 1H), 3.49 (br. m, 5H), 3.16 (br. m, 2H), 3.00 (br. m, 3H), 2.89 (br. m, 1H), 2.74 (br. m, 3H), 1.95 (br. m, 1H), 1.86 (br. m, 2H), 1.43 (br. m, 1H).
1-(4-chlorobenzyl)-2-({3-[(4-propylpiperazin-1-yl)carbonyl]piperidin-1-yl}methyl)-1H-indole dihydrochloride 1.3.2.1(13). Yield is 78%. LCMS (M+H)+ 493,495. 1H NMR (DMSO-d6, 400 MHz) δ 11.12 (br. m, 2H), 7.63 (d, J=7.6 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.17 (m, 1H), 7.09 (m, 1H), 6.99 (br. m, 1H), 6.93 (d, J=8.0 Hz, 2H), 5.69 (br. s, 2H), 4.51 (br. s, 2H), 4.37 (br. m, 1H), 4.06 (br. m, 1H), 3.59 (m, 1H), 3.41 (br. m, 5H), 3.14 (br. m, 2H), 2.98 (br. m, 4H), 2.85 (br. m, 1H), 1.96 (br. m, 1H), 1.86 (br. m, 2H), 1.70 (br. m, 2H), 1.43 (br. m, 1H), 0.90 (br. m, 3H).
1-Methyl-2-({3-[(4-propylpiperazin-1-yl)carbonyl]piperidin-1-yl}methyl-1H-indole dihydrochloride 1.3.2.1(14). Yield is 47%. LCMS (M+H)+ 383. 1H NMR (DMSO-d6, 400 MHz) δ 11.19 (br. m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.22 (m, 1H), 7.07 (m, 1H), 6.83 (br. m, 1H), 4.56 (br. s, 2H), 4.37 (m, 1H), 4.05 (m, 1H), 3.87 (s, 3H), 3.61 (m, 1H), 3.44 (br. m, 5H), 3.14 (br. m, 2H), 2.98 (br. m, 4H), 2.86 (br. m, 1H), 1.98 (br. m, 1H), 1.86 (br. m, 2H), 1.70 (br. m, 2H), 1.44 (br. m, 1H), 0.89 (br. m, 3H).
Preparation of a medicament in the form of tablet. Starch (1600 mg), grained lactose (1600 mg), talcum (400 mg) and [1-(1-methyl-1H-indol-2-ylmethyl)-piperidin-4-yl]-(4-propyl-piperazin-1-yl)-methanone dihydrochloride 1.3.1.1(14)*2HCl (1000 mg) were mixed together and pressed in a brick. Prepared brick was crushed to granules and riddled through sieves, gathering granules of 14-16 mesh size. The obtained granules were pelletised in tablets of suitable form of 560 mg by weight each.
Preparation of a medicament in the form of capsules. [1-(1-Methyl-1H-indol-2-ylmethyl)-piperidin-4-yl]-(4-propyl-piperazin-1-yl)-methanone dihydrochloride 1.3.1.1(14)*2HCl was carefully mixed with lactose powder in ratio 2:1. The prepared powdery mixture was packed on 300 mg into gelatinous capsules of suitable size.
Preparation of a medicament in the form of compositions for intramuscular, intraperitoneal or hypodermic injections. [1-(1-Methyl-1H-indol-2-ylmethyl)-piperidin-4-yl]-(4-propyl-piperazin-1-yl)-methanone dihydrochloride (500 mg) 1.3.1.1(14)*2HCl was dissolved in the mixture of chlorobutanole (300 mg), propylene glycol (2 ml), and water for injections (100 ml). The prepared solution was filtered and placed in 1 ml ampoules which were sealed up and sterilized in an autoclave.
The invention could be used in medicine, veterinary, biochemistry.
Number | Date | Country | Kind |
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2010130863 | Jul 2010 | RU | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/RU11/00533 | 7/19/2011 | WO | 00 | 3/5/2013 |