The method of obtaining derivatives mevalonate
(57) Abstract:Usage: in the pharmaceutical industry. The inventive product is metaloplastikovye derivatives of f-crystals I. Reagent 1: derived pyrazolo-[3,4-b] -pyridine-5-yl-3.5-di-hydroxy - hept-6-ene acid f-ly II. Conditions: cyclization in an organic solvent in the presence of a dehydrating agent. table 4. The structure of the compounds f-ly I, II: The invention relates to new mevalonate with pyrazolopyrimidine ring, processes for their preparation, pharmaceutical compositions containing them and their pharmaceutical use, especially as antihyperlipidemic, hypolipoproteinemia and antiatherosclerotic agents, and to intermediate products useful for their preparation and methods of producing such intermediates.It is known that some metabolicheskie products of fermentation, such as compactin, CS-514, mevinolin or semi-synthetic derivatives or fully synthetic derivatives thereof are inhibitors of HMG-CoA reductase which is an enzyme that limits the speed in the biosynthesis of cholesterol.Clinical way it was proved that With 514 and mevinolin I the treatment or prevention of diseases of the coronary arteriosclerosis or atherosclerosis.Studies have found that megalonychidae derivatives having pyrazolopyrimidine ring, the corresponding dihydroxy carboxylic acids and salts and their esters have high inhibitory activity of cholesterol biosynthesis, in which HMG-CoA reductase acts as an enzyme, limiting the reaction rate.New megalonychidae derivative of the proposed method is represented by formula I:
where R1C1-6-alkyl or phenyl;
R3(C1-C5)-alkyl, cyclopropyl.WITH1-6-alkyl includes, for example, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.In addition, these compounds may have at least one or two asymmetric carbon atoms and may have at least two to four optical isomers. The compound of formula I include all of these optical isomers and their mixtures.The compounds of formula I obtained by cyclization of compounds of formula II
II where R1, R2and R3defined above.This reaction is a reaction formation mevalonate formulas I through reaction dehydra the Le at reflux while removing the formed water, or by adding a suitable hydrating agent such as molecular sieve.In addition, the dehydration reaction can be carried out in dry methylene chloride using lactonases agent such as carbodiimide, preferably water-soluble carbodiimide such as para-toluensulfonate N-cyclo - hexyl-N'-(2'-)methylmorpholine(ethyl)carbodiimide at a temperature 10 35aboutWith, preferably 20 25aboutC.Source mevalonate formula II can be obtained by reduction of compound of formula III
R (III) where R1R2and R3see above.The reduction of metacarbonate formula III, passes through various recovery agents. This reaction involves the restoration of the carbonyl with the help of example: sodium borohydride, cyanoborohydride sodium, zinc borohydride, vitaminlerin, DIBORANE, tert.-butylaminoethyl, complex pyridine-borane, dicyclohexylurea, vexillary, 9-borabicyclo (3,3,1)nonane, diazepinonelor or three-Deut.-butylbromide lithium in the appropriate dihydroxyquinoxaline formula II.This reaction can be carried out in a solvent selected from hydrocarbons, halogenated hydrocarbons, C1-4-alcohols, ethers and mixtures thereof, at a temperature (-100) (50aboutC) borane and sodium borohydride are used at low temperature. In addition, the Erythro-form, having a biologically superior activity can be successfully obtained using alkoxyalkane such as detoxication or amoxicillian or sodium borohydride.This reaction can be carried out using a mixture solvent WITH1-4-alcohol and tetrahydrofuran at a temperature (-80) (-50)aboutWith, preferably (-72) (-68)aboutC.The compounds of this invention exhibit high inhibitory activity against cholesterol biosynthesis, in which HMG-CoA reductase acts as an enzyme, limiting speed, as shown by the results of the test data below, and thus can suppress or reduce the amount of cholesterol in the blood as lipoprotein. Thus, the compounds of this invention are useful as therapeutic agents against hyperlipidemia, hyperlipoproteinemias and atherosclerosis. They can be transformed into a variety of suitable prom or ready forms of drugs depending on the assignment method. The compounds can be administered in the form of free acids or in the form physiologically hydrolyzable and acceptable esters or lactones, or pharmaceutical is in the form of the proposed connection (by itself) or in the form of powders, granules, tablets or capsules formulated by mixing the proposed connection with a suitable pharmaceutically acceptable carrier, comprising a binder such as hydroxypropylcellulose, syrup, Arabian gum, gelatin, sorbitol, gum tragakant, polyvinylpyrrolidone or SMS-Sa, excipient, such as lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine or powder, crystalline cellulose, a lubricating agent such as magnesium stearate, talc, polyethylene glycol or silica, and a disintegrator, such as potato starch.However, the pharmaceutical composition of the present invention is not limited to such a oral appointment, it is applicable for parenteral purposes. For example, it may be administered in the form of a suppository formed using an oil base material such as cocoa butter, polyethylene glycol, lanolin or triglyceride of fatty acids, transdermal therapeutic base formed with a liquid paraffin, white vaseline, higher alcohols, ointment Macrogol, hydrophilic ointment or gidrogennogo base material, injectable formulation prepared with use the main material, distilled water, distilled water for injection and excipient, such as lactose or corn starch, or preparative forms for appointment through the mucous membrane, such as mucous membrane of the eyes, nasal mucosa and the mucosa of the mouth.In addition, the proposed connection can be combined with the basic ion exchange resins, which are capable of binding bile acids and still not absorbed by the gastrointestinal tract.Daily dose of the compounds of formula (I-III) is 0.05 to 500 mg, preferably 0.5 to 50 mg for an adult. It is appointed to receive from one to three times a day. The dose may of course vary depending on age, weight and condition of the patient.Testing A. Inhibition of cholesterol biosynthesis from acetate in vitro.The enzyme solution was prepared from the liver of male Wistar rats, which was inserted cannula and output of bile within 24 h, the Liver was cut in twilight and microsome assay and the fraction floating on top, can precipitate 40 80% solution of ammonium sulfate (soup-fraction) were prepared from liver homogenate according to the modified method Knauss et al. Cihelka) were incubated for 2 h at 37aboutWith 200 µl reaction mixture containing ATP, 1 mmol glutathione; 6 mm glucose-1-phosphate, 10 mmol NAD; 0.25 mmol NADP; 0.25 mmol, SOA; 0.04 mmol, 0.2 mmol (2-14C) sodium acetate (0,2 Ci) with 4 μl of a solution of the test compounds dissolved in water or dimethyl sulfoxide. To stop the reaction and saponification, the reaction mixture was added 1 ml of 15% EtOH KOH and the mixture was heated at 75aboutC for 1 h is Not capable of saponification of the lipids were extracted with petroleum ether and were counted introduced radioactivity14C. Inhibiting activity of the compounds expressed by the indicator 50 1G.The trial of the Century, the Inhibition of the biosynthesis of cholesterol in the cells of the culture.Cells ner C2 was sown on 12-mesh plates and were incubated with the modified bagle medium Dulbecco (DME) containing 10% of bovine embryo serum (PBS) at 37aboutWITH 5 CO2up until the cells became confluent within approximately 7 days. Cells were exposed to IU medium containing 5% serum with a lack of content lipoprotein (LpDS), obtained by the method of ultracentrifugation for almost 24 hours. The medium was replaced with 0.5 ml of fresh 5% LpDS containing DME, before analysis and dobavleniya compounds were added to 0.2 Ci (2-13C) sodium acetate (20 µl). After additional incubation for 4 h with (2-14C) sodium acetate medium was removed and cells were washed with saline, buferizovannyiy phosphate (PBS), cooled at 4aboutC. the Cells were ascariasis rubber wand and collected in tubes with PBS and deserialise with 0.2 ml of 0.5 norms KOH at 37aboutC. a healthy dose of liquid from the stage of thererofre was used for analysis of protein, and the rest of malalas 1 ml of 15% EtOH-KOH at 75aboutC for 1 h Neomy-tion lipids were extracted with petroleum ether and were counted14With radioactivity. The results of the count were tested in cellular protein designated by the value of the use of frm/mg (disintegrations per minute/mg protein. The inhibitory activity of the compounds was expressed by the value of 50 1C.Test C. Inhibition of cholesterol biosynthesis in vivo.The male rats Sprague-Dawley weighing about 150 g were given food in the form of conventional food Purina and water as needed and prior to use to test for inhibition of in vivo biosynthesis of cholesterol in rats subjected to the impact of the lighting scheme 12 h light/12 h darkness (2:00 afternoon 2:00 to noon dark time). Animals were divided into groups consisting of five body (0.4 ml/100 g body weight) was dissolved in water or suspendibility in 0.5% methylcellulose and administered orally for 2-3 hours before dusk (8:00 PM), when cholesterol biosynthesis in rats reached a maximum. The control rats were administered only water or media. After 90 min after the appointment of the samples, rats were injected with intraperitoneal 10 MK CI (2-14C) sodium acetate in a volume of 0.2 ml each. After 2 h took samples of blood and immediately separated the serum. Total lipids were extracted according to the method of Folch and others and amylases mixture Et-CON. Unsaponifiable lipids were extracted with petroleum ether, counted the radioactivity introduced in unsaponifiable lipids.Inhibitory activity was observed as the percentage decrease in the number of counts (a measure background radiation) in the test groups (disintegrations/ minute /2 ml serum/2 h) compared to the control group.Regarding the proposed connection indicators inhibitory activity against cholesterol biosynthesis, in which HMG-CoA reductase serves as a limiting speed of the enzyme was measured using the above tests a and B. the Results are shown in table. 1, 2, 3, 4. Additionally presents the results of measurements using test With.Indicators inhibitory activity of the reference compound by using tested and the prevalence of relative activity based on the activity of CS-514 testing And, which was estimated equal to 1.The structure of the reference compounds
< / BR>Inhibitory activity of the test-1: reference connection CS-514; 1C 50 (molar concentration) of 1.1 x 10-8< / BR>P R I m e R 1 (E) -7-[4'-(4"-forfinal)-1',3'-dimethyl-6'-]1"-methylethyl[pyrazolo(3,4-b)pyridi n-5'-yl] -3,5-dihydroxyphenyl-6 - ANOVA acid (compound 1-2-1).0.25 g (of 0.53 mmol) of ethyl-(E)-7-[4'-(4-forfinal)-1',3'-dimethyl-6']1"-methylethyl[-pyrazolo(3,4-b) pyridin-5'-yl]-3,5-dihydroxide-6-enoate was dissolved in 3 ml of ethanol and to the solution was added dropwise 1,06 ml of 0.5 N. aqueous solution of sodium hydroxide. The ethanol was distilled under reduced pressure, and then to the mixture was added 3 ml of distilled water. The solution was washed with diethyl ether. The aqueous layer was carefully kind of balanced out 1% hydrochloric acid and was extracted with diethyl ether. The ether layer was dried over anhydrous magnesium sulfate and was supariwala under reduced pressure, giving the desired compound.The amount of 0.12 g (yield 90%)
PAMR (DSS-d6S million dollars. 1,29 (D. I 7 Hz, 6N) and 1.83 (C. 3H), to 2.1-2.3 (m, 2H), 2,4-2,6 (m, 1H), 3.0 to 3.6V (m, 4H), 3.96 points (C. 3H), 4,3-4,8 (m 2N), is 5.2-5.6 (m, 1H), 6,3 and 6.6 (m, 1H), 7,2-7,4 (m, 4H), 11,5-12,0 (Shir.s, 1H).P R I m m e R 2. In the same way as described in example 1 were Polo-2-5 (DMSO-d6) million dollars. 0,8-1,1 (m, 4H), 1,4-1,8 (m, 2H), 1,89 (s, 3H), of 2.1 to 2.6 (m, 4H), of 3.0 to 3.8 (m, 2H), 3,98 (s, 3H), from 4.3 to 4.6 (m, 1H), 5,3-5,7 (m, 1H), from 6.4 to 6.8 (m,1H), 6,9-to 7.3 (m, 4H).P R I m e R 3. (E)-trance-6-2'-[4"-(4"'-forfinal-1",3"-dimethyl-6")-1"'-methylethyl] pyrazolo(3,4-b)pyridin-5-yl(ethinyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-Piran - 2-on (compound 1-3-1).130 mg (0.29 mmol) of the compound 1-2-1 was dissolved in 6 ml of dichloromethane and to the solution was added 125 mg (0.29 mmol) of n-toluensulfonate N-cyclohexyl-N'(2'- methylmorpholinium)-carbodiimide. The mixture is stirred at room temperature for 2 h, and then subjected to distillation under reduced pressure to remove solvent to dryness. The residual oil was purified using thin-layer chromatography on silica gel (eluent: a mixture of hexane and ethyl acetate 9:1 (volume/volume)) to give pure desired compound in the form of colorless viscous oily substance. The number of 48 mg (yield 39%).P-NMR (CDCl3) million dollars. 1,33 (D. I=6,8 Hz, 6N), 1,4-1,5 (m, 1H), 1.6 to 1.7 (m, 2H), 1.93 and (C. 3H), 2,5-2,6 (m, 1H), 2,68 (DD. I=18 Hz, j=5 Hz, 1H), 3,39 (Gately, I= 6,8 Hz, 1H), 4,07 (C. 3H), 4,1-4,2 (m, 1H), 5,1-5,2 (m, 1H), 5,31 (DD. I= 16 Hz, j=6 Hz, 1H), 6,61 (DD. I 16 Hz, j=1.5 Hz, 1H), 7,1-7,3 (m, 4H).P R I m e R 4. The method described in example 3 were obtained compound 1-3-5 1-3-17. The physical data of these soy is (m 1H), 1,65-1,70 (m, 1H), 1,76 (C. N), 1,84 (C. 3H), 2,08 (C. 1H), 2,59-to 2.65 (m, 1H), 2,71 (doctor, doctor I=18 Hz, j=5 Hz, 1H), 3,41 (Gately, I=7 Hz, 1H), 4,23-the 4.29 (m, 1H), 5,15-to 5.21 (m, 1H), 5,58 (DD. I 16 Hz, I 6 Hz, 1H), 6,67 (DD. I 10 Hz, 1 Hz, 1H), 7,10-7,25 (m, 1H). The METHOD of OBTAINING MEVALONATE DERIVATIVES of General formula
< / BR>where R1WITH1WITH6-alkyl or phenyl;
characterized in that the derived pyrazolo(3,4-b)pyridin-5-yl-3,5-dihydroxide-6-ene acid of General formula
< / BR>where R1R3have the specified values,
is subjected to cyclization in the medium of organic solvent in the presence of a dehydrating agent.
R(I) where R1hydrogen, alkyl or hydroxyl radical;
R2hydrogen, linear or branched C1-C4-alkyl, foralkyl, cycloalkyl, alkyloxyalkyl or alkylamino radical;
R3WITH1-C4-alkyl, and R4and R5different and mean hydrogen or C1-C4-alkyl;
or R3hydrogen or alkyl, or cycloalkyl and R4and R5individually, each means hydrogen;
R6hydrogen or fluorine;
n is 1 or 2, or their salts, possess antibacterial property
(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where
-A1= AND2- A3= AND4- bivalent radical having the formula
-CH=CH-CH=N (a-5) or
n=1 or 2
IN - NR4or CH2< / BR>R4is hydrogen or C1-C6alkyl
L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula
-Alk - R5(b-1),
-Alk - Y - R6(b - 2),
-Alk - Z1- C(=X) - Z2- R7(b-3), or
-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)
Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;
R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;
Y is O or NH;
Z1or Z2each independently NH or a direct link X-O
each Аlk independently - C1-C6alcander
FIELD: medicine, phthisiology.
SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.
EFFECT: higher efficiency of differential diagnostics.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.
EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.
26 cl, 2 tbl, 253 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes diazepane derivative of the general formula (I)
or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.
EFFECT: valuable medicinal properties of compound.
5 cl, 5 tbl, 6 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:
wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.
EFFECT: valuable medicinal properties of compound.
13 cl, 1 dwg, 4 tbl, 16 ex
FIELD: organic chemistry, cardiology, pharmacy.
SUBSTANCE: invention describes compounds of the formula (I)
wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.
EFFECT: valuable medicinal properties of compounds.
41 cl, 1 tbl, 8 ex
SUBSTANCE: the present innovation deals with preventing hemodynamic complications at restoring circulation in a prolongly ischemized limb, or due to premeditated tourniquet application during operative interference. For this purpose, 5-12 min before the onset of circulatory restoration it is necessary to start intravenous injection of antihistamine and glucocorticosteroid preparations, followed by drop-by-drop infusion of inhibitors of proteolytic enzymes which should be continued after tourniquet removal, as well. The method provides tourniquet shock and tourniquet shock-associated complications along with developing the chance for increasing the duration period of operation.
EFFECT: higher efficiency of prophylaxis.