D-tartrate(-)cis-6(s)-phenyl-5(r)-[4-(2-pyrrolidin-1 ylethoxy) phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol, method thereof, a method of preventing states susceptible agonists of estrogen, the pharmaceutical composition


(57) Abstract:

Described is a method of obtaining D-tartrate(-)CIS-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol, which is useful as an agonist of estrogen and can be used to prevent mammals conditions susceptible agonists of estrogen, such as osteoporosis, cardiovascular disease when hyperlipidemia, prostate disease, hypercholesterolemia, obesity, breast cancer, endometriosis. 4 C. and 7 C.p. f-crystals.

The present invention relates to D-tartrate, (- ) CIS-6(S)- phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8 - tetrahydronaphthalen-2-ol, which is useful as an agonist of estrogen, and how to obtain it.

Obtaining (-)CIS-6(S)-phenyl-5(R)-[4- (2-pyrrolidin-1 ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol in the form of a free base and its salts with R-(-)-1,1'-binaphthyl-2,2'-dailybriefing (R-binap) described in Patent Application U.S. serial number 08/369954, the text of which is incorporated herein by reference.

The objective of this invention to provide a salt of tartaric acid D-tartrate (-)CIS-6(S)-phenyl-5(R)-[4-(2 - pyrrolidin-1 ylethoxy)-phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol.

Friend the phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol, including:

1) dissolving racemic or partially optically enriched CIS-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy)- phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol in boiling aqueous ethanol to obtain a solution;

2) adding to the said solution of equimolar amount of D-tartaric acid dissolved in aqueous ethanol, to obtain a second solution;

3) the specified cooling the second solution and

4) collection of the product obtained in stage 3.

Another aspect of this invention is to provide pharmaceutical compositions comprising D-tartrate (-)CIS-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8 - tetrahydronaphthalen-2-ol and pharmaceutically suitable carrier.

Another aspect of this invention is to provide methods of treatment or prevention of diseases or symptoms that respond to treatment or prevention by agonists of estrogen, which include the introduction to a mammal in need of such treatment or prevention, an effective amount of D-tartrate, (- ) CIS-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy) phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol.

Racemic CIS-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8 - tetrahydronaphthalene perform the separation of the racemate by crystallization of the salt of R-(-)-1,1'-binaphthyl - 2,2'-dailybriefing (R-binap), as described in Patent Application U.S. serial number 08/369954. Since R-binap is not salt, suitable for pharmaceutical applications, R-binap product need to translate a free base and, ultimately, in a pharmaceutically suitable salt.

Found that D-tartaric acid forms in aqueous ethanol salt of the 1:1 racemic or partially optically enriched CIS-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy)phenyl]-5,6,7,8 - tetrahydronaphthalen-2-I.

After cooling, the desired (-) isomer is separated in the form of a substance and its easy to assemble, thus ensuring pharmaceutically suitable salt of (-)CIS-isomer in high yield and purity by a single-stage reaction. The preferred solvent for this procedure is a water-ethanol, the preferred mixture is 95% aqueous ethanol.

This invention is easy to implement by dissolving racemic or partially optically enriched CIS-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8 - tetrahydronaphthalen-2-ol with equimolar amounts of D-tartaric acid in boiling aqueous ethanol, preferably 95% ethanol. The amount of solvent should be sufficient for complete dissolution of the salt. About the ardenia to room temperature the desired (-) CIS-isomer is separated in the form of a substance. This product has an optical frequency of about 95%. Washing with 95% ethanol by boiling under reflux yields a product with an optical purity of > 99%.

The compound of this invention is a valuable agonist of estrogen and useful for oral contraceptive; relief of menopausal symptoms; prevention of threatening or habitual miscarriage; relief of dysmenorrhea; relief of dysfunctional uterine bleeding; relief of endometriosis; aid in ovarian development; treatment of acne; reduce excessive growth of body hair in women (hirsutism); prevention and treatment of cardiovascular diseases; prevention and treatment of atherosclerosis; prevention and treatment of osteoporosis; treatment of benign prostatic hyperplasia and obesity in carcinoma of the prostate (prostatic carcinoma obesity) and suppression of postpartum lactation. This connection also has a beneficial effect on the level of plasma lipids and, thus, useful in the treatment and prevention of hypercholesterolemia.

Despite the fact that the compound of the present invention is an estrogen agonist in bone, it is an antiestrogen in breast tissue and can therefore be poleznye endometriosis, caused by surgical intervention, are identical to those described in: Jones, Acta Endoerinol (Copenh) 106:282-8. Use of adult female rats, Charles River Sprague-Davley CD(200-240 g). Do oblique ventral skin incision and muscle wall of the body. Cut out a segment of the right corniculate process of the uterus (right uterine horn), separated from the myometrium and endometrium cut segment along. Section endometrial 5x5 mm with epithelial lining connected with the wall of the body, attached to the four corners of the muscle, use polyester thread (Ethiflex 7-0). The criterion for the viability of the transplant is the accumulation of fluid, similar to those occurring in the uterus in the estrogenic stimulation.

Three weeks after transplantation of endometrial tissue (+3 weeks) conduct laparotomy animals, measured with a compass volume of Explant (length x width x height) in mm and start processing. Animals injected subcutaneously for 3 weeks from 10 to 1000 mg/kg/day of the compounds according to this invention. Animals that carry the endometrial explants and serve as control for 3 weeks injected subcutaneously with 0.1 ml/day of corn oil. After the 3-week treatment period (+6 weeks) wire is spruce) animals put to death; again measure the Explant. Conduct statistical analysis of the volume of Explant through variance analysis.

Influence on the weight of the prostate

3-month-old male rats of Sprague-Dawley daily for 14 days administered by subcutaneous injection or filler (10% ethanol in water), or estradiol (30 μg/kg), or testosterone (1 mg/kg) or the compound according to this invention (n=6/group). After 14 days, animals kill, remove the prostate and determine the wet weight of the prostate. Determine the average weight and determine statistical significance (p < 0,05), using t-student test, compared with the group treated filler.

The compound of the present invention reduces the weight of the prostate in comparison with the filler. Testosterone has no effect, whereas estrogen at a dose of 30 mg/kg reduces the weight of the prostate.

The density of bone minerals

The density of bone minerals (bone mineral density), measurement of the mineral content of bones, the calculations for the strength of the bones of more than 80%. Loss of bone mineral substances with age and/or due to illness reduces bone strength and makes it more prone to fracture. Mineral soderm way it is possible to quantify changes at the 1% level. The authors used DEXA to assess changes in bone mineral substances, caused by a deficiency of estrogen, with subsequent oophorectomy (surgical removal of the ovaries) and the processing of filler, estradiol (E2), keoxifene (raloxifene) or other agonists of estrogen. The objective of this study is to assess the dimensions by way DEXA ability of compounds of the present invention to prevent damage to the bones due to lack of estrogen.

Conduct bilateral oophorectomy or sham surgery (sham surgery) at 4-6-month-old females (S-D) rats and give them to recover from anesthesia. Daily for 28 days to rats injected via subcutaneous injection or orally via a stomach tube with varying doses (for example, 10 to 1000 μg/kg/day) compound of the present invention. All connections are weighed and dissolved in 10% ethanol in sterile saline. After 28 days, the rats are killed, remove the thighs and released from the meat. Hip is placed on the device Hologic QDR1000W (Hologic, Inc. Waltham, MA) to determine the density of the bone mineral substance in the peripheral portion of the thigh at the site of 1-2 cm from the far end of the femur, using the information from Hologic software with high resolution the spine in the peripheral region of the femur. Each group contains at least 6 animals. For each animal receives the average value of the density of bone minerals and using t-test, determine statistical differences (p<0,05) from results group by oophorectomy and stimulation surgery, the treated filler.

In vitro binding of the estrogen receptor

In vitro binding of the estrogen receptor, which determines the ability of compounds according to the present invention to displace [3H] -estradiol from the estrogen receptor of the person obtained by recombinant methods in yeast, is used to determine the binding properties of the estrogen receptor compounds according to this invention. In this study use the following materials: (1) a buffer for the study of TD-0,3 (containing 10 nm Tris, pH of 7.6, 0.3 M potassium chloride, and 5 mm DTT, pH 7,6); (2) used radioactive ligand is [3H]-estradiol obtained from New England Nuclear; (3) used an inactive ligand is estradiol obtained from Sigma; (4) recombinant estrogen receptor human, hER.

A solution of the compound prepared in TD-0,3 4% DMSO and 16% ethanol. Tretirovanie estradiol dissolved in TD-0,3 ER so to total protein was 1,10 mcg in each analyzed cell. Using tablets for micrometrology in every incubat add 50 ál inactive estradiol (nonspecific binding) or a solution of the compound, 20 µl titiraupenga estradiol and 30 μl of hER solutions. Each tablet contains three copies of the full binding and different concentration of the compound. Tablets incubated overnight at 4oC.

Then the reaction accession stop adding and mixing 100 ml of 3% hydroxyapatite in 10 mm Tris, pH 7.6 and inquira for 15 minutes at 4oC. the Mixture is centrifuged and the precipitate is washed four times by 1% Triton-X100, 10 mm Tris, pH of 7.6. Precipitation of hydroxyapatite suspended Ecoscint and measure radioactivity, using the method of beta-scintigraphy. Define values for all three measured points (the number of pulses per minute pulse/min).

Calculate specific binding by subtracting the number of pulses. /min for non-specific binding (defined as the impulses that remain after separation of the reaction mixture containing the recombinant receptor, radioactive ligand and its excess ligand) of the total number of pulses/min (defined as iniecting ligand).

The ability of the compounds are determined by definitions IC50(the concentration of compound required for 50% inhibition of total specific binding estradiol treated). Determine specific binding in the presence of various concentrations of compounds and calculated as a percentage of specific binding from the total specific binding of radioactive legend. Data are presented as percent inhibition compound (linear scale) relative to the concentration of the compound (logarithmic scale).

Effect on total cholesterol

The effect of the compounds of the present invention on total cholesterol in the plasma is determined as follows. Blood samples are taken by heart puncture under anesthesia at 4-6-month-old females (S-D) rats undergoing bilateral oophorectomy, and treated with the investigational compound (10 - 1000 mg/kg/day, for example, subcutaneously or orally for 28 days or treated filler within the same time) or carry out the simulation of surgical intervention. The blood is placed in a tube containing 30 μl of 5% EDTA (10 μl of EDTA/1 ml of blood). After centrifugation speeds of 2500 rpm./min for 1st set for enzymatic determinations from Sigma Diagnostics (Procedure # 352).

Impact on obesity

10-month-old female Sprague-Dawley rats weighing about 450 g conduct the simulation of surgical intervention or oophorectomy (OVX), and introduce them orally filler, 17A levonorgestrel in a dose of 30 mg/kg/day or the compound of the present invention at the dose of 10 - 1000 mg/kg/day for 8 weeks. In each sub-group is 6 to 7 rats. The next day studies to determine the body composition for all rats, using dual x-ray absorptiometry = dual energy x-ray absorptiometry (Hologic QDR - 1000/W) equipped with the software to scan the entire body, which shows the ratio of the mass of body fat and body mass without fat.

The reduction of body fat indicates that the connection according to this invention useful for the prevention and treatment of obesity.

Means against prostate cancer, breast cancer, obesity, cardiovascular disease, hypercholesterolemia and osteoporosis containing compound of the present invention, it is possible to introduce animals, including humans, orally or parenterally in the form of conventional preparative forms, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions and Siro is olivani, hypercholesterolemia and osteoporosis containing compound of the present invention, it is possible to obtain well-known methods using conventional organic or inorganic additives such as a filler (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polipropilenglicol, polyvinylpyrrolidone, gelatin, gum Arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g. starch, carboxymethyl cellulose, hydroxypropylmethyl, nizkozameshhennoj hydroxypropylcellulose, sodium bicarbonate, sodium phosphate, calcium phosphate or calcium citrate), lubricants (e.g. magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulphate), agent for taste and smell (e.g., citric acid, menthol, glycine, orange powder), preservatives (e.g. sodium benzoate, sodium bisulfate, methylparaben or propylparaben), a stabilizer (for example, citric acid, sodium citrate or acetic acid), suspendisse agent (for example, methylcellulose, polyvinylpyrrolidone or aluminum stearate), a dispersing agent (e.g. white petrolatum or polyethylene glycol). The amount of active ingredient in the pharmaceutical composition may be at a level that provides the desired therapeutic effect; for example from 0.1 to 50 mg standard dosage form for oral and parenteral use.

Usually the active ingredient you can enter from one to four times per day at a standard dosage of from 0.1 to 50 mg for patients-people, but the above dosage may be properly varied depending on the age, bodyweight and medical symptoms of the patient and type of admission. Patients-people preferred dose of 0.25 to 25 mg Preferable is a single dose per day. Used herein, the term "treatment" includes warning (prevention and palliative care.

Getting 1

Racemic CIS-6-phenyl-5(R)-[4-(2 - pyrrolidin-1 ylethoxy)-phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol

Stage A.

CIS-1-{ 2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl) phenoxy] ethyl} pyrrolidine. A solution of the hydrochloride 1-{2-[4-(6- methoxy-2-phenyl-3,4-dihydronaphthalene-1-yl)-phenoxy] ethyl}pyrrolidine (nofaxingpaydayloan) (1.0 g, of 2.16 mmole) in 20 ml of absolute ethanol containing 1.0 g of palladium hydroxide on carbon, hydronaut when the pressure 3,515 kg/cm21H-NMR (CDCl3): 3,50 - of 3.80 (m, 3H), 3,85 (s, 3H), 4,20 - and 4.40 (m, 3H), 6,80 - 7,00 (m, 3H), MS: 428 (P++1).

Stage B.

To a solution of 400 mg (0,94 mmole) of the product of stage a in 25 ml of methylene chloride at 0oC add drop by drop under stirring of 4.7 ml (4.7 mmole) of 1.0 M solution tribromide boron in methylene chloride. After three hours at room temperature, the reaction mixture was poured into 100 ml of rapidly stirred saturated aqueous sodium bicarbonate. The organic layer is separated, dried over sodium sulfate, filtered and concentrated, getting 287 mg (yield 74%) specified in the header of the substance in the form of free base.1H-NMR (CDCl3): at 3.35 (DD, 1H), 4.00 points (t, 2H), 4,21 (d, 1H), 6.35mm (AB Quartet, 4H). The corresponding hydrochloride salt get processing solution base excess 4 N. HCl in dioxane, followed by evaporation to dryness and rubbing with ether. MS: 415 (P++1).

Below is described an alternative method useful for Obtaining 1.

Stage A.

1-{2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalene-1-yl)phenoxy] ethyl}pyrrolidine. A mixture of anhydrous CeCl3(138 g, 560 mmol) and THF (500 ml) was vigorously stirred for 2 hours. In a separate flask was cooled to -78oC solution of 1-[2-(4-bromophenoxy)ethyl] Pirro is cut 15 minutes the solution was added to a cooled to -78oC pasta CeCl3through the tube and the reaction mixture is stirred for 2 hours at -78oC. a Solution of 6-methoxy-1-teraluna (65,2 g, 370 mmol) in THF (1000 ml) at -78oC is added through a tube to the reagent arylaryl. The reaction mixture is allowed to slowly warm to room temperature and stirred for a full 16 hours. The mixture is filtered through a layer of celite. The filtrate was concentrated in vacuo and add 3 N. HCl (500 ml) and Et2O (500 ml). After stirring for 15 minutes, the layers separated. Then the aqueous layer was washed twice by Et2O. the combined organic layers are dried (MgSO4), filtered and concentrated, obtaining 6-methoxy-1 - tetralone (22 g). The aqueous layer was alkalinized to pH 12 by 5 N. NaOH and add a 15% aqueous (NH4)2CO3(1000 ml). The aqueous mixture is extracted twice by CH2Cl2. The organic solution is dried (MgSO4), filtered and concentrated, obtaining a brown oil. Impurities distilled (110 - 140oC and 0.2 mm RT.cent.), receiving the product (74 g, 57%).1H-NMR (250 MHz, CDCl3): 7,27 (d, J=8.7 Hz, 2H), 6,92-of 6.99 (m, 3H), 6,78 (d, J= 2.6 Hz, 1H), 6,65 (DD, J=8.6 and 2.6 Hz, 1H), of 5.92 (t, J=4,7 Hz, 1H), 4,15 (t, J=6.0 Hz, 2H), 3,80 (s, 3H), equal to 2.94 (t, J=6.0 Hz, 2H), 2,81 (t, J=7,6 Hz, 2H), 2,66 (m, 2H), is 2.37 (m, 2H), of 1.84 (m, 4H).

Stage Century.

Hydrochloride 1-{ 2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalene-1-yl) phenoxy] ethyl}pyrrolidine (nofaxingpaydayloan). To the mixture 1-{2-[4-(2-bromo-6-methoxy-3,4-dihydronaphthalene-1-yl) -phenoxy] ethyl}pyrrolidine (19 g, 44 mmole), phenylboronic acid (7.0 g, 57 mmole) and tetrakis(triphenylphosphine) palladium (1,75 g and 1.51 mmole) in THF (300 ml) was added Na2CO3(13 g, 123 mmole) in H2O (100 ml). The reaction mixture is heated to boiling under reflux for 18 hours. The layers are separated and the organic layer was washed with H2O, ichnevogo solids. The residue is dissolved in a mixture of 1:1 CH2Cl2and EtOAc (250 ml) and add 1 N. HCl in Et2O (100 ml). After stirring for 2 hours the product is left to crystallize out of solution and collected by filtration 11 g of substance. Concentration of the mother liquor to half volume gives in addition to 7.3 g of product.


CIS-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl) phenoxy] ethyl} pyrrolidine. Hydrochloride 1-{2-[4-(6- methoxy-2-phenyl-3,4-dihydronaphthalene-1-yl)phenoxy]ethyl}pyrrolidine (nofaxingpaydayloan) (75 g, 162 mmole) is dissolved in 1000 ml of EtOH and 300 ml of MeOH. Add dry Pd(OH)2on carbon and the mixture hydronaut for 68 hours at 50oC and a pressure of 3,515 kg/cm2(50 lb/in2) on the vibrator Parr (Parr shaker). The catalyst is filtered off using celite and the solvents removed in vacuo. The obtained white solid was dissolved in CH2Cl2and the solution washed with saturated aqueous NaHCO3. The organic solution is dried (MgSO4), filtered and concentrated, obtaining off-white solid (and 62.6 g, 90%).

Stage D.

CIS-6-phenyl-5-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol. The mixture of CIS-1-{ 2-[4-(6-methoxy-2 - phenyl-1,2,3,4-t is ri 100oC for 15 hours. The solution is cooled and the resulting white precipitate collected by filtration. The hydrobromide salt (9.6 g, 69 %) was dissolved in CHCl3/MeOH and stirred with saturated aqueous NaHCO3. The layers are separated and then the aqueous layer was extracted by CHCl3/MeOH. The combined organic layers are dried (MgSO4), filtered and concentrated, obtaining the product as off-white foam.1H-NMR (250 MHz, CDCl3):? 7.04 baby mortality (m, 3H), 6,74 (m, 2H), 6,63 (d, J=0.3 Hz, 2H), 6,50 (m, 3H), 6,28 (d, J=8.6 Hz, 2H), 4,14 (d, J=4.9 Hz, 1H), 3,94 (t, J=5.3 Hz, 2H), 3,24 (DD, J= 12,5 and 4.1 Hz, 1H), 2.95 and (m, 4H), 2,78 (m, 4H), and 2.14 (m, 1H), of 1.88 (m, 4H), by 1.68 (m, 1H).

Example 1

D-tartrate (-) CIS-6(S)-phenyl-5(R)-[4-(2-pyrrolidin-1 ylethoxy) phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

< / BR>
Racemic amine of Example 1 (5 g, 12,1 mmole) in a mixture of 95:5 absolute ethanol/water (50 ml) is treated with a solution of D-tartaric acid (1,83 g, 12,1 mmole) in a mixture of 95:5 absolute ethanol/water (20 ml). The mixture is heated at a calm boiling under reflux and get a homogeneous solution. After heating for 10 minutes the mixture is allowed to cool and stirred at ambient temperature (~25C) during the night. Salt precipitated as a white solid and is collected by filtration with suction Ave is in vacuum (house vacuum) at room temperature (~25C) receiving 2,77 g (81% of theoretical yield). Study by way of chiral high-performance liquid chromatography shows an optical purity of 95:5 with a predominance of the desired enantiomer.

White solid (2,77 g) is suspended in a mixture of 95:5 absolute ethanol/water (28 ml), heated to boiling under reflux and stirring for 3.5 hours. After cooling to room temperature the mixture granularit during the night. White solid is collected by filtration with suction, washed with ethanol (15 ml) and dried with suction. After drying in vacuum (house vacuum) at room temperature get 2,48 g (95% of theoretical yield) of selected salts with an optical purity > 99:1, according to the study by way of chiral high-performance liquid chromatography.

1. D-tartrate (-) CIS-6 (S)-phenyl 5 (R)-[4-(2-pyrrolidin-1 ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol.

2. The method of obtaining D-tartrate, (- ) CIS-6 (S)-phenyl-5 (R)-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol, characterized in that it includes:

a) dissolving racemic or partially optically enriched CIS-6-phenyl-5-[4-(2-pyrrolidin-1 ylethoxy)phenyl] -5,6,7,8-etrg equimolar amount of D-tartaric acid, dissolved in water standard, to obtain a second solution,

C) cooling the specified second solution, and

g) collecting the product obtained at stage Century.

3. A method of preventing a mammal States susceptible agonists of estrogen, characterized in that it comprises the administration to a mammal of a connection on p. 1 in an effective amount.

4. The method according to p. 3, wherein the specified condition is osteoporosis.

5. The method according to p. 3, wherein the specified state is a heart-coolitem disease with hyperlipidemia.

6. The method according to p. 3, wherein the specified condition is a disease of the prostate.

7. The method according to p. 3, wherein the specified condition is hypercholesterolemia.

8. The method according to p. 3, wherein the specified condition is obesity.

9. The method according to p. 3, wherein the specified condition is breast cancer.

10. The method according to p. 3, wherein the specified condition is endometriosis.

11. Pharmaceutical composition having the effect of agonist/antagonist ESTRO as the active ingredient contains the connection p. 1 in an effective amount.


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