Pyrazolopyrimidine compound for treating erectile dysfunction
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a compound (I) or its pharmaceutically acceptable salt, which possess properties of selective phosphodiesterase inhibitors, and can be used for treating male erectile dysfunction. In compound (I) R1 represents C1-C6alkyl; R2 represents C1-6alkyl; R3 represents C1-C6alkyl; R4 represents C1-C6 alkyl; R5 means H. The above salt is formed by the compound of formula (I) and an acid specified in citric acid, oxalic acid, hydrochloric acid, sulphuric acid, phosphoric acid, maleic acid, fumaric acid, tartaric acid, hydroxysuccinic acid, succinic acid, methane sulphonic acid or n-toluene sulphonic acid. A preferential compound is 5-[2-ethoxy-5-(4-methyl-1-homopiperazinylsulphonyl)]phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
EFFECT: preparing the pharmaceutically acceptable salt that possesses the properties of selective phosphodiesterase inhibitors.
7 cl, 1 tbl, 5 ex
The technical field to which the invention relates
The present invention relates to the technical field of pharmaceutics and, in particular, relates to a new kind of fast-acting, having a lasting effect of the compounds to prevent or treat erectile dysfunction.
The level of technology
Erectile dysfunction (ED) is a type of disease characterized by the inability to develop erection of the penis, the inability to make a stronger erection or inability to sustain an erection, which can lead to failure of the sexual functions. There are many reasons for erectile dysfunction. The first reason, which may lead to erectile dysfunction, is a psychological reason such as bad relationships in pairs or mental stress caused by any reasons. The second reason is a physiological cause, such as a breakdown of the center of erection. Severe disease, in particular long-term medical condition of some important organs such as the liver, kidneys, heart, lungs, can also affect the mental control of sexual physiology. The incidence of erectile dysfunction increases with increasing life expectancy. In accordance with the review of the normal population in the U.S., the incidence is 8% in adults�'s men while in China, the incidence is approximately 10%.
There are currently many types of ways to treat erectile dysfunction, among them the oral administration of drugs is the most appropriate. Commercial drugs for oral administration for the purpose of erectile dysfunction mainly consists of sildenafil (trade name viagra), tadalafil (brand name: cialis), udenafil (trade name: levitra).
Sildenafil, tadalafil and udenafil all of them are selective inhibitors of cyclic guanosinmonofosfat (cGMP)-specific phosphodiesterase-5 (PDE5). Physiological mechanism of erection of the penis is associated with the release of nitric oxide (NO) in the cavernous body of the penis during sexual stimulation. NO activates guanilatziklazu, and then leads to increased levels of cyclic guanozinmonofosfata (cGMP), to relaxation of smooth muscles in the cavernous body and to the retention of blood. The concentration of cGMP in tissues may be regulated by phosphodiesterase, and present in the cavernous body in the greatest number is a phosphodiesterase cGMP-specific phosphodiesterase-5 (PDE-5). Medicines, such as sildenafil, increasing the effects of nitric oxide by inhibiting PostGIS�erase type 5 (PDE5), which breaks down cGMP in the cavernous body. When the local release of NO is increased under the influence of sexual stimuli medicines, such as sildenafil can inhibit PDE-5, to increase the level of cGMP in the cavernous body, relax smooth muscles, forcing the blood to flow in the cavernous body, and then to initiate an erection.
With the help of clinical trials in many countries, it is shown that sildenafil is effective for erectile dysfunction, caused by different reasons, and, thus, is a safe, effective, convenient medicine for treatment of ED. However, medicines such as sildenafil, have some clinical side effects, such as headache, flushing, dyspepsia, nasal obstruction and puropse, and can even cause cardiovascular diseases such as lowering blood pressure in the supinated position and decrease cardiac output. In addition, clinical studies have shown that when sexual function is carried out after the introduction of sildenafil, the incidence of heart disease, including symptoms such as asthma, dizziness, nausea and the like, will increase and this can lead to cardiogenic sudden death.
Currently, as �oomaeda in EP0463756, CN1358722A, CN1283624A and the like, in the world there are many methods of synthesis of sildenafil, which can be divided into two types.
(1) First, synthesize the intermediate compound 1-methyl-2-phenyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he then introduced sulphonylchloride group in the benzene ring by interacting with sulphonylchloride, and, finally, it is associated with N-methylpiperazine and form a salt with citric acid.
(2) Carry out the reaction between 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide and 2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)benzoyl chloride, and then get sildenafil by closing the ring.
In addition, the authors found that when using the new compounds are obtained by using N-methylhomopiperazine instead of N-methylpiperazine for synthesis of sildenafil for the implementation of experiments on animals, the duration of effective impact of the drug from the new connection is greatly improved compared with sildenafil when administered the same dose during the treatment of erectile dysfunction, and the timing of its impact becomes short, and its toxicity and side-effects are reduced.
For this reason, the present invention will be described 2-Fe�alprazolamonline derivative for the treatment of erectile dysfunction in men.
Summary of the invention
The present invention describes the selective inhibitors of phosphodiesterase-5 (PDE5). Compared with sildenafil or udenafil, its advantage lies in the fact that the timing of exposure is short, and the length of the effective impact of the drug is large.
Described is also the use of compound (I) or its pharmaceutically acceptable salts, or medical compositions containing these compounds, for treating or preventing erectile dysfunction in men.
where R1represents H, C1-C6alkyl, C1-C6foralkyl or C3-C6cycloalkyl;
R2represents H, halogen, C1-C6alkyl, C1-C6foralkyl or C3-C6cycloalkyl;
R3represents C1-C6alkyl, C1-C6foralkyl or C3-C6cycloalkyl;
R4represents H, C1-C6alkyl, C3-C6cycloalkyl; C1-C6alkyl which may be substituted with hydroxy, amino;
R5represents one or more identical or different of the following substituents such as H, halogen, hydroxy, amino, C1-C6alkyl, C3-C6cycloalkyl.
With�organisations of the formula (I) can form salts with acids or acidic substances, such as citric acid, oxalic acid, hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, tartaric acid, malic acid, succinic acid, methanesulfonic acid, p-toluensulfonate acid and the like.
Compounds of formula (I) is selected from
In the synthesis of compounds of formula (I) previous interim connection of the medicinal product 5-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he used to get the corresponding sulphonylchloride by reaction of phenol sulfonuvannya dyfenilsulfo chloride in. Its specific schema is like below.
5-(2-ethoxy)phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he interacts with sulphonylchloride, the resulting product is then associated with a N-methylhomopiperazine, white crystals separated, filtered, dried, and then receive the product.
In addition, provision of medical tablet containing compound (I), and its preparation method, where the tablet can contain multiple pharmaceutical� acceptable carriers, including pharmaceutically common diluting agent, binder, disintegrating agent, lubricant.
Thus the diluting agent includes starch, powdered sugar, dextrin, lactose, pre-gelatinizing starch, microcrystalline cellulose, inorganic salts, mannitol; a binder includes distilled water, ethanol, a suspension of starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose and ethylcellulose, hydroxypropyl methylcellulose, gelatin solution, sucrose solution and the solution of polyvinylpyrrolidone; disintegrating agent include dry starch, carboxymethylated starch, hydroxypropyl cellulose with a low degree of substitution, cross stitched polyvinylpyrrolidone, cross stitched sodium carboxymethylcellulose; a lubricant includes magnesium stearate, Aerosil, powdered calcic, gidrirovannoe vegetable oil, the polyethylene glycol and magnesium dodecyl sulfate.
5-[2-ethoxy-5-(4-methyl-1-homopiperazine)]phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he citrate (ED9001) is the preferred compound of the present invention. As has been revealed in studies of the effectiveness of adult sexually Mature male rats Sprague-Dawley, ED9001 demonstrates a discernible impact �and increased amounts of sexual contact, compared with the control group with the introduction of a solution (P<0,05), and shows a certain ratio of dose-effect. This suggests that it has the potential impact of improving the sexual appetite and sexual function. In addition, the timing of exposure is shorter and the length of the effective impact of the drug.
Detailed description of the invention
sulphonylchloride (50 ml) was added in a 100-ml three-neck flask with stirrer, 5-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he (to 31.2 g (0.1 mol)) was added in portions with stirring in an ice bath. The reaction is exothermic and is carried out for 12 hours. The reaction solution was slowly poured into ice water (100 g), white solid product was separated, filtered, dried. Get white solid product (30 g) with a yield of 76%.
5-[2-ethoxy-5-(4-methyl-1-homopiperazine)]phenyl-1-methyl-3 - propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-she
5-(2-ethoxy-5-chlorosulfonyl)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he (to 20.5 g (0.05 mol)), dry chloroform (205 ml) is added�t 500-ml three-neck flask with stirrer, was stirred in an ice bath, and further added N-methylhomopiperazine (5,65 g), the pH was adjusted to about 9 using diisopropylethylamine, and the reaction is carried out for 12 hours. The reaction mixture was concentrated, added ethyl acetate (200 ml), washed with water, dried, and then get white solid product (22,5 g) with a yield of 92.2 per cent.
5-[2-ethoxy-5-(4-methyl-1-homopiperazine)]phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he (of 4.88 g (0.01 mol), acetone (50 ml) was added in a 100-ml three-neck flask with stirrer, stirred in an ice bath, add citric acid (1.92 g), the reaction is carried out for 12 hours, white crystals separated, filtered with suction, dried, and then draw a white solid product (6,23 g) with a yield of 90.5 per cent.
|The name of the original substances (excipients)||Dosage|
|transversely crosslinked sodium carboxymethylcellulose||1|
|dehydrate calcium sulphate||20|
The mass of the original substances and auxiliary substances is generally 400 g, crushed, sieved, and then mixed well, granulated, pressed into the form 1000 tablets, 50 mg each.
Investigation of the effectiveness of drugs against erectile dysfunction
80 post-pubertal female rats pure line Sprague-Dawley whose body weight is 200±12 g and aged 8 weeks, opt for research. Bilateral ovariectomy performed under anesthesia with intraperitoneal injection of 10% chloralhydrate, and penicillin (20000 units/kg) �lead in the form of intramuscular injections after surgery for 3 days. The study is carried out 2 weeks after ovariectomy, estradiolelisaut (200 units/kg) administered by intramuscular injection 48 hours before the test, and progesterone (2 mg/kg) administered as an intramuscular injection for 4 hours before the study in order to synchronize rut for copulating research.
130 adult sexually Mature male rats the clean lines of Sprague-Dawley whose body weight is 200±13 g and aged 8 weeks, select and stabilize for 2 weeks to use. They randomly divided into control group with the introduction of the solvent (0.5% sodium carboxymethylcellulose), positive control group (sildenafil), the study group with the introduction of the drug at high/medium/low dosage ED9001, 20 rats in each group. Methods of administration, division into groups and the conditions of introduction are as follows.
Method of administration: intragastric administration;
Volume of injection: 1 mg/100 g of body weight;
The control group with the introduction of the solvent: 0.5% solution of CMC-Na;
The group with the introduction of sildenafil: the concentration of the drug or 0.44 mg/ml;
The group with high dosage ED9001: the concentration of the drug 0,88 mg/ml;
The group with average dose: the concentration of the drug or 0.44 mg/ml;<> The group with low dosage: concentration of the drug of 0.22 mg/ml.
Observation is carried out at 7:00-10:00 p.m., and the lighting in the room weaken with a red lamp for observation. When the research begins, male rats are first placed in the cells, and then observe within 10-20 minutes, the results are shown in Table 1 below.
The results of research on the effectiveness ED9001 against ED
|Group in relation to drug||The number of rats||Dosage (mg/kg body weight)||The latent period of sexual behavior|
|The number of sexual contacts|
|The number of sex sessions (times)|
|the control group with the introduction of solvent||16||13,1±4,7||24±7||18±7|
|the group with the introduction of sildenafil||15||4,4||12,5±6,5||27±6||24±7|
|the group with low dosage ED9001||12||2,2||12,1±3,6||31±9||24±7|
|the group with an average dosage ED9001||11||4,4||14,4±7,5||26±9||21±7|
|the group with high dosage ED9001||14||8,8||14,2±4,9||32±9||27±10|
In accordance with the results ED9001 shows discernible impact on improving quantities of sexual contact compared with the control group with the introduction of the solution at half the dosage of sildenafil (P<0.05) and shows a certain ratio of dose-effect. This suggests that it has potential impact on enhancing sexual appetite and sexual function.
The above described only the preferred examples of the present invention, not intended to limit the scope of the present invention. The main technical contents of the present invention is determined in the framework of the claims. Any t�detailed technical solutions or ways, by other will be considered as falling within the scope of the claims if they are such, as defined by the framework of the claims of the present application or by equivalent changes.
1. The compound (I) or its pharmaceutically acceptable salt
where R1represents C1-C6alkyl;
2. The compound according to claim 1, where the specified salt formed by a compound of formula (I) and an acid selected from citric acid, oxalic acid, hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, tartaric acid, malic acid, succinic acid, methanesulfonic acid or p-toluensulfonate acid.
3. The compound according to claim 1, where R1is methyl or ethyl, R2represents n-propyl, R3represents ethyl or n-propyl, R4is methyl or ethyl.
4. The compound according to claim 1, wherein the compound of formula (I) is a
5. Pharmaceutical composites prevent or treat erectile dysfunction in men containing the compound of formula (I) according to any one of claims. 1-4, or its pharmaceutically acceptable salt and pharmaceutically acceptable diluting agent or carrier.
6. Method of preparation of pharmaceutical compositions for treating or preventing erectile dysfunction in men, comprising the step of mixing a compound of formula (I) according to any one of claims. 1-4, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluting agent or carrier.
7. Use of a compound of formula (I) according to any one of claims. 1-4, or its pharmaceutically acceptable salt for the preparation of pharmaceutical compositions for treating or preventing erectile dysfunction in men.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to novel compounds of formula (I), possessing properties, making it possible to inhibit phosphorylation of AKT (proteinkinase B; PKB), to versions of method of their obtaining, as well as to intermediate products for their obtaining. In particular compounds can be applied in treatment of different tumours and/or metastases, as well as in case parasitic diseases such a malaria. In formula (I), R1 stands for -L-phenyl or -L-heteroaryl, with term "heteroaryl" standing for bicyclic radical, containing from 9 to 12 units, L stands for either linear or branched alkyl, containing 1-6 carbon atoms, optionally substituted with hydroxyl, or CO group, or group L'-X, where L' stands for linear or branched alkyl, containing 1-6 carbon atoms, and X stands for oxygen or sulphur atom; with phenyl and heteroaryl being optionally substituted with one or several radicals, similar or different, selected from halogen atoms, -NRxRy, alkoxy and alkyl; with said alkyl being optionally substituted with one or several halogen atoms; R2 stands for hydrogen atom or alkyl; R3 stands for alkyl, optionally substituted with one or several halogen atoms; R4 stands for hydrogen atom or halogen atom; with NRxRy being such that Rx and Ry form together with nitrogen atom, which they are bound to, cyclic radical, including 3-10 units, and optionally oxygen atom; and all alkyl or alkoxy radicals, mentioned above, are linear or branched and contain 1-6 carbon atoms.
EFFECT: compounds can be applied as active component for obtaining medications, intended for treatment or prevention of disease, characterised by deregulation of protein- or lipidkinase activity.
25 cl, 3 tbl, 43 ex
SUBSTANCE: invention relates to compounds of structural formula
having Aβ42 secretion inhibiting activity. In formula I , hetaryl I is a five- or six-member heteroaryl group containing 1-3 heteroatoms selected from O, S or N, hetaryl II is a five- or six-member heteroaryl group containing 1-3 heteroatoms as defined above for hetaryl I, or is a bicyclic ring system containing 1-4 heteroatoms selected from S, O or N, where at least one ring is aromatic by nature, R1 is C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted with a halogen, or a halogen; R2 is a halogen, C1-7-alkyl, C1-7-alkoxy, hydroxy, C1-7-alkyl substituted with a halogen, C1-7-alkyl substituted with a hydroxy, or benzo[1,3]dioxolyl or is -(CHR)p-phenyl, optionally substituted with a halogen, C1-7-alkyl, C1-7-alkoxy, S(O)2-C1-7-alkyl, cyano, nitro, C1-7-alkoxy substituted with a halogen, dimethylamino, -(CH2)p-NHC(O)O-C1-7-alkyl or C1-7-alkyl, substituted with a halogen. The values of radicals R, R3, R4,p, n, m, o are given in the claim.
EFFECT: invention relates to a method of producing said compounds, a medicinal agent containing said compounds and a method of treating Alzheimer's disease, cerebral amyloid angiopathy, Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), vascular dementia, dementia pugilistica or Down syndrome, associated with β amyloid activity.
21 cl, 283 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to 5,5-condensed heteroarylene compounds IIIB, where U2, V1, V2 and W1 are selected from O, N, NH, S or CR3a; U1, W2, X1 and X2 represent C or N; R1 and R2 represents hydrogen, -C(O)CH(NR1bR1c)R1a, -C(O)CH(N(R1c)C(O)OR1b)R1a or -C(O)OR1a; R3a represents hydrogen or R3; R3 represents halogen or -C(O)OR1a; L1 and L2 are such as given in invention formula, each Z1 and Z2 represents bond or -O-; each Rla, R1b and R1c represents hydrogen, C1-6 alkyl or C6-14 aryl; or Rlb and Rlc together with N atom, which they are bound to, form 5-6-membered heterocyclyl; q, r, s, t and u equal 1. Invention also relates to pharmaceutical compositions, containing 5,5-condensed heteroarylene compounds, and methods of treating or preventing HCV infection.
EFFECT: 5,5-condensed heteroarylene derivatives, possessing inhibiting activity with respect to hepatitis C virus.
43 cl, 42 ex
SUBSTANCE: invention relates to a method of obtaining a formula compound. The method includes a stage of binding a formula compound with a formula compound in the presence of a base with the formation of the formula (I) compound. In formula (I) stereochemical configurations in the positions, marked with asterisks, are relative; Rb represents hydrogen; R00 represents a C1-10 aliphatic group or a C6-14 aryl group, including one-three rings; Rd, Re, Re', Rf, Rh, Rh', Rk represent hydrogen; Rg represents chlorine, fluorine, iodine or bromine; Rm represents a protective hydroxyl group; values of radicals Ra, R*, Rc are given in the invention formula. In formulas (II) and (III) Ra, Rb, Rc, Rd, Re, Re', Rf, Rg, Rh, Rh', Rj, Rk and Rm are such as determined in formula (I) and R1 represents -CH2CHO. The invention also relates to methods of obtaining compounds of formulae (V), (VI), (VId) and to a compound of the structural formula (IIa). Structural formulae of compounds (V), (VI), (VId), (IIa) are given in the invention formula.
EFFECT: method makes it possible to carry out synthesis in a regioselective way and use the obtained product without purification.
15 cl, 1 tbl, 26 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed invention relates to ethinyl derivatives of formula I, where X represents N or C-R1; Y represents N or C-R2; Z represents CH or N; R4 represents 6-membered ring, containing 0, 1 or 2 nitrogen atoms, possibly substituted with 1-2 groups, selected from halogen, lower alkyl, lower alkoxy or NRR'; R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower cycloalkyl or represents 5-6-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O and N; R2 represents hydrogen, CN; R and R' independently on each other represent hydrogen; or their pharmaceutically acceptable salts or acid-addition salts. Invention also relates to pharmaceutical composition, possessing activity of positive allosteric modulator of mGluR5 receptor, including effective quantity of at least one invention compound, and to application of invention compounds for manufacturing medication for treatment or prevention of diseases, associated with positive allosteric modulators of mGluR5 receptor.
EFFECT: obtained are novel compounds, which can be applied as positive allosteric modulator of mGluR5 receptor.
14 cl, 51 ex
SUBSTANCE: invention describes a method of producing and a method of purifying dialkyl pemetrexed of formula (I) , having antifolate action. The compound can be used to treat non-small-cell cancer and, coupled with cisplatin, to treat malignant pleural mesothelioma of the lungs. The method includes reacting a carboxylic acid of formula (II) with a diester of glutamic acid of formula (III) or an acid-addition salt thereof. The process is carried out in the presence of a substituted triphenyl phosphate of formula (IV) , a base and a solvent. In formulae (I) and (III) each R1 and R2 independently represents alkyl groups. In formula (IV) X, Y and Z assume values given in the claim.
EFFECT: use of safe, mild, cheap, non-oxidising and easy to handle triphenyl phosphate simplifies the process and enables to obtain, for example, diethyl pemetrexed with purity higher than 99%.
14 cl, 12 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.
EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.
15 cl, 16 ex
SUBSTANCE: claimed invention relates to a method of obtaining methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid and benzosulphonate of methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid, which includes the interaction of methyl ether of 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid with an oxidiser and, optionally, processing the reaction product in acidic conditions, as well as to intermediate compounds and .
EFFECT: simplification and reduction of the price of the obtaining method due to the reduction of the number of stages.
13 cl, 8 ex
SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.
EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.
26 cl, 2 tbl, 40 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to new substituted aminotetrahydropyranes of structural formula or to their pharmaceutically acceptable salts , and , wherein V is specified in groups having the formulas below, Ar represents phenyl unsubstituted or substituted by one to five halogen atoms, each of R1 and R2 is independently specified in C1-C6alkyl; R3 is specified in a group consisting of C1-C6alkyl; cyano; tetrazolyl; -C(O)OC1-C6alkyl and -C(O)NH2; wherein C1-C6alkyl is substituted by 1-4 substitutes independently specified in a group consisting of OH; -C(O)NH2 and -CO2H. The declared compounds can be dipeptidylpeptidase-IV inhibitors and can be applicable in treating or preventing diseases involving the enzyme dipeptidylpeptidase-IV, such as diabetes, and especially type 2 diabetes mellitus.
EFFECT: invention also refers to a pharmaceutical composition containing the above compounds, and using the above compounds and compositions for preventing or treating the diseases involving the enzyme dipeptidylpeptidase-IV.
12 cl, 14 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.
EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new chromone derivatives of general formula
wherein: R1 represents one or more identical or different substitutes on a benzene ring, each of which independently represents a hydrogen atom, or a halogen atom, or C1-4 alkoxy group, or OH group. or group -O(CH2)nO-, wherein n=1 or 2, R2 represents a hydrogen atom, or C1-4 alkyl group; A and B independently represent either a nitrogen atom, or a carbon atom; R3 represents a hydrogen atom or one or more identical or different substitutes specified in a group consisting of: a halogen atom, C1-4 alkyl group, C1-4 alkoxy group, group -O(CH2)nO-, wherein n=1 or 2, group NO2, group NHSO2R4, group NHR5, OH group, C1-4 halogenoalkyl group, CN group, or R3 makes a ring condensed with a benzene ring bearing it, specified in a group consisting of indole, benzimidazole, carbostyril, benzoxazolone and benzoxazolone and benzimidazolone, R4 represents C1-4 alkyl group, or C1-4 dialkylamino group, or C1-4 alkoxyalkyl group, or C1-4 dialkylaminoalkyl group, R5 represents a hydrogen atom, or C1-4 alkylcarbonyl group, or C1-4 alkoxycarbonyl group, and to its pharmaceutically acceptable salts, as well as to methods for preparing them, and to based pharmaceutical compositions, and to using them as a therapeutic agent for central nervous system disorders, as long as they possess the D3 dopaminergic ligand properties.
EFFECT: preparing the compositions for treating central nervous system disorders, as long as they possess the D3 dopaminergic ligand properties.
17 cl, 1 dwg, 2 tbl, 33 ex
SUBSTANCE: invention relates to medicine, namely to urology, and deals with treatment of erectile dysfunction. For this purpose pharmaceutical composition, containing activated potentiated form of antibodies to prostate-specific antigen and as additional enhancing component - activated potentiated form of antibodies to endothelial NO-synthase.
EFFECT: introduction of claimed composition provides efficient treatment of erectile dysfunction due to anti-inflammatory, antiproloferative and vascularisation-improving properties of its components.
9 cl, 1 ex
SUBSTANCE: invention refers to a new pharmaceutical composition in the form of spray for oral administration, containing an aqueous solution of sildenafil citrate as an active substance in the amount of 3-30 wt %. The composition contains stabilising agents in the form of pharmaceutically acceptable calcium salts taken in an amount required to reduce pH to 3.0 to 6.0. The calcium salts are specified in a group consisting of calcium lactate pentahydrate, calcium lactate trihydrate, calcium gluconate, calcium malate, calcium glycolate, calcium chloride hexahydrate and calcium chloride dihydrate. What is also described is a method for preparing the composition by introducing the pharmaceutically acceptable calcium salts as the stabilising agents into the aqueous solution of sildenafil citrate.
EFFECT: pharmaceutical composition in the form of oral spray is free from organic solvents and applicably for sexual dysfunction.
13 cl, 8 ex
SUBSTANCE: androgens are introduced into the body under laboratory control of testosterone. An androgen source is dermal administration of the preparation androgel 5 g in the interval of 48-72 hours in a pulse mode for 2-3 months. After laboratory control additionally involving the serum analysis for intestinal cell-stimulating and follicle-stimulating hormones, sex hormone binding globulin, prostatic specific antigen, sperm fertility, the dermal administration of androgens is continued for another 2-4 months. If the above values fall beyond the norms, the prescribed androgens are withdrawn for 2-4 months.
EFFECT: invention provides preventing side effects of substitution androgen therapy.
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to new phenylpyrimidone derivatives of formula I possessing the properties of a phosphodiesterase type 5 (PDE5) inhibitor. The compounds of formula I can be used for treating various vascular disorders, such as erectile dysfunction, pulmonary arterial hypertension, etc. In formula each R1 and R2 independently means H; C1-C10alkyl; halogen; CF3; CN; OR5; NR6R7; NHCOR8; aryl; or C1-C4alkyl optionally substituted by OR5; Z means OR3; R3 means C1-C6alkyl or C1-C3alkyl, substituted by C1-C3alkoxy group; R4 means SO2NR6R7; NR9R10, providing NR9R10 is other than NH2; COR11; OR12; or R4 means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH and C1-C6 alkyl; or R4 means 5- or 6-merous cyclic monosaccharide group; R5 means C1-C6alkyl; C1-C4alkyl optionally substituted by C1-C4alkoxy group; each R6 and R7 independently means H, OH, C1-C6alkyl, C1-C6alkoxy group, C3-C6alkenyl, C3-C6cycloalkyl, adamantyl, C3-C8lactamyl, aryl, Het or (CH2CH2O)jH, wherein j is 1-3; or each R6 and R7 independently means C1-C6alkyl, optionally substituted by OH, C1-C4alkoxy group, SO3H, SO2NR13R14, SO2R16, NR13R14, aryl, Het or 5-6-merous heterocyclyl; or each R6 and R7 independently means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of C1-C6 alkyl and C1-C6alkyl substituted by hydroxyl; or R6 and R7 together with a nitrogen atom attached whereto form 5-7-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH, COOR8, (CH2CH2O)jH, wherein j is 1-3, C1-C4alkoxy group, Het and C1-C6alkyl substituted by aryl; or R6 and R7 together with a nitrogen atom attached whereto form a glucosyl amino group, an amino acid residue, a residue of an amino acid ester or an amino amide residue. The other radical values are specified in the patent claim.
EFFECT: invention refers to pharmaceutical compositions based on the above compounds, using them, methods for preparing the compounds, and intermediate products.
18 cl, 2 tbl, 224 ex
FIELD: chemistry, pharmacology.
SUBSTANCE: medication for prevention and treatment of andrological diseases represents dried alcohol extract of gonads of sea urchin Strongylocentrotus droebachiensis, obtained by successive processing of gonads with two-phase extractant chloroform-ethanol, then with 95% ethyl alcohol, keeping with periodical mixing, solid residue after separation of liquid extract is poured with 70% ethyl alcohol and kept with mixing, separated and dried under specified conditions.
EFFECT: medication is efficient for prevention and treatment of andrological diseases.
3 cl, 4 tbl, 6 ex
SUBSTANCE: common procedure is used to prepare platelet rich plasma to be administered at three stages. At the first stage, the platelet rich plasma is injected using an insulin syringe along a lateral surface of a penis in a bilateral direction: the autoplasma 1.0 ml is injected in a proximal, medial and distal direction; totally the autoplasma 3.0 ml is injected into each cavernous body. At the second stage, the autoplasma 2.0 ml is injected under an albugineous coat of the penis under ultrasonic control. The third stage involves injecting the autoplasma into sciatic-cavernous muscles 1.0 ml each with the penis slightly massaged to distribute the autoplasma. The procedure is repeated for three times every 1 week. The method enables stimulating the growth and development of the cavernous vessels promoting its revascularisation, improves the penis innervation, as well as enhances the functional capacities of the endothelium. The higher tone of the sciatic-cavernous muscles promotes better venous-occlusive component.
EFFECT: regular spontaneous sleeping erections, improved morning erections, higher quality of patient's sex life.
1 cl, 1 ex
SUBSTANCE: invention refers to medicine, specifically urology. A method involves the complex postoperative rehabilitation. From the 10th postoperative day, the patient is exposed to electric myostimulation at current intensity to pelvic floor muscle contraction, frequency 30-50 Hz, modulation depth 100% for 10-15 minutes. The therapeutic course is 12-20 daily procedures. In one month from the operation, the ischiocavernous and bulbospongiosus muscles are trained. That involves doing three exercises thinking of 'penis contraction'. The first exercise represents 5 tensions with maximum intensity (100%), length 5 seconds and tension pauses 90 seconds. The second exercise represents 5 tensions with intensity 50% of maximum intensity, length 15 seconds and tension pauses 20 seconds. The second exercise represents 5 tensions with intensity 30% of maximum intensity, length 30 seconds and tension pauses 20 seconds. The exercises are done min. 3 times, once a week in the morning and evening. They are added with doing the interval exercises for lower extremity muscles. The exercises include 15-minute warm-up activities and doing the exercises of intensity 70-80% of maximum intensity, 50-60% of maximum heart rate, repeated for 5 times with 3-minute pauses. The exercises are done not less than 3 times. From the second postoperative month, a phosphodiesterase-5 inhibitor is administered.
EFFECT: method provides improving the quality of erection ensured by erection compression of the superficial veins of penis and blood outflow blocking from the cavernous body and prolonged therapeutic effect.
4 cl, 1 ex
SUBSTANCE: invention relates to organic chemistry and specifically to novel 7-piperidinoalkyl-3,4-dihydroquinolone derivatives and a pharmaceutically acceptable salt or hydrate thereof, where R is a hydrogen atom or a C1-6-alkyl group; A1, A2 and A3, which can be identical or different, are each a hydrogen atom, a halogen atom; X is a C1-6-alkylene group; Y is a bond or a C1-6-alkylene group; Z is a bond or a C1-6-alkylene group, where the C1-6-alkylene group can be substituted with a phenyl group; W is a bond or an oxygen atom; and Cy is a phenyl group or a pyridyl group, where the phenyl or pyridyl group can have 1-3 substitutes which can be identical or different and are selected from a group consisting of a halogen atom, a cyano group, a C1-6-alkyl group, C1-6-alkoxy group, where the C1-6-alkyl group or C1-6-alkoxy group can be substituted with 1-3 halogen atoms, and a C2-6-alkanoyl group. The invention also relates to a pharmaceutical composition and a preventive or therapeutic drug based on the compound of formula (I) .
EFFECT: obtaining novel 7-piperidinoalkyl-3,4-dihydroquinolone derivatives, having antagonistic action on MCH receptor.
6 cl, 4 tbl, 10 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to oxazolopyramidine compounds of formula I, where A represents O; R1 is selected from phenyl or pyrimidine, which are optionally substituted with R11; R2 represents phenyl, which is optionally substituted wby 1-3 ring carbon atoms with similar or different substituents R22, R11 represents halogen; R22 is selected from hydroxy group, (C1-C4)-alkyl, which is optionallysubstituted with 1-3 atoms of fluorine, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-; m equals 2. Invention also relates to pharmaceutical composition, which contains formula I compounds, and to method of obtaining formula I compounds.
EFFECT: formula I compounds, intended for activation of EDG-1 receptor and applied for wound healing.
15 cl, 2 tbl, 2 ex