Derivatives of diphenylazethidinone, medicinal agents comprising these compounds and their using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of diphenylazathedinone of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another (0-C30)-alkylene-L wherein one or some C-atoms of alkylene residue can be substituted with -O-, -(C=O)- or -NH- and, except for, R1-R6 can represent hydrogen atom (H), fluorine atom (F), and L represents compound of the formula: , and their pharmaceutically tolerated salts also. Compounds of the formula (I) elicit hypolipidemic effect and can be used in therapeutic aims. Also, invention describes a medicinal agent and its using.

EFFECT: valuable medicinal properties of compounds.

7 cl, 31 ex

 

The invention relates to substituted diphenylacetylene, their physiologically tolerable salts and physiologically functional derivatives.

Diphenylacetylene (as, for example, ezetimibe), as well as their use for the treatment of hyperlipidemia, arteriosclerosis and hypercholesterolemia have already been described [cf. Drugs of the Future, 2000, 25(7): 679-685].

The objective of the invention is to provide new compounds exhibiting lipid-lowering effect, suitable for use in therapeutic purposes.

First task was to search for new compounds, which are compared with the compounds described in the prior art, absorbed would be very insignificant. Under very low absorbability means putting absorbability less than 10%, preferably less than or equal to 5%.

New connections must first have a lower absorption than ezetimib.

When reduced absorbability of pharmaceutical active substances, as a rule, are significantly less side effects.

The invention relates to compounds of formula I,

where means

R1, R2, R3, R4, R5, R6 independently of each other (C0-C30-alkylene-L, and one or more C atoms alkyl residue may be replaced by-O-, -(C=O)-, -CH=CH,≡,- N((C -C6)alkyl) -, or-NH-;

H, F, Cl, Br, I, CF3, NO2, CN, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogens may be replaced by fluorine; SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n may be n=0-6, and the phenyl residue may be substituted up to two times F, Cl, Br, OH, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;

NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, and n may be n=0-6, and the phenyl ring can be from one to three times substituted by F, Cl, Br, I, OH, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;

L represents a

R7 is methyl, ethyl, propyl, butyl;

R8 is H, OH, NH2, NH-(C1-C6)-alkyl;

R9 is methyl, ethyl, propyl, butyl;

R10 is methyl, ethyl, propyl, butyl;

and there is always at least one of the residues R1-R6 must have a value (C0-C30-alkylene-L, and one or more C atoms of alkyl residue may be replaced by-O-, -(C=O)-, -CH=CH-, -C≡C-, -N((C1-C6)-alkyl)- or-NH-,

and their pharmaceutically tolerated salts.

Preferred compounds of formula I where at least one of the remainder of R1-R6 has a value (C0-C30-alkylene-L, and one or more C atoms of alkyl residue may be replaced by-O-, -(C=O)- or-NH-.

Especially preferred compounds of formula I in which one of the residues R1 or R3 has the value (C0-C30-alkylene-L, and one or more C atoms alkyl residue may be replaced by-O-, -(C=O)- or-NH-. Exclusively preferred compounds of formula I in which one of the residues R1 or R3 has the value -(CH2)0-1-NH-(C=O)0-1-(C3-C25-alkylene-(C=O)0-1-NH-L, and one or more C atoms alkyl residue can be substituted atom O.

Binding of one of the residues R1-R6, with the remainder of L is preferably in the meta-position of ring C group L.

Pharmaceutically tolerated salts due to its high races is foremost in water as compared with the initial or basic compounds are particularly suitable for medical applications. These salts must be pharmaceutically tolerable anion or cation. Suitable pharmaceutically tolerated acid additive salts of the compounds according to the invention are salts of inorganic acids as hydrochloric acid, Hydrobromic, phosphoric, metaphosphoric, nitric, sulfo and sulphuric acids, and organic acids, such as acetic acid, bentalha-, benzoic, citric, econsult-, fumaric, gluconic, glycolic, sotynova, lactic, lactobionic, maleic, malic, metasolv-, succinic acid, p-toluensulfonate, wine and triperoxonane acid. For medical purposes especially preferably applied chloride. Suitable pharmaceutically portable basic salts are salts of ammonia, alkali metal salts (like sodium and potassium salts), and salts of alkaline-earth metals (as magnesium salt and calcium).

Salts with pharmaceutically unbearable anion in the framework of the present invention are also seen as useful intermediates for obtaining or purification of pharmaceutically-borne salts and/or for use in non-therapeutic purposes, for example for use in vitro.

Used herein, the term "physiologically functional derivative" refers to any physiologically tolerated derivative of a compound according to the image is the shadow, for example an ester, which when used mammal, such as man, is able (directly or indirectly) to form such a compound or its active metabolite.

Another aspect of the present invention are prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to compounds according to the invention. These prodrugs can be both active and inactive.

Compounds according to the invention can exist in different polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention is included in the scope of the invention constitute the subject matter of the invention.

Hereinafter all references to "compound(I) according to the formula (I)" means a compound(I) of the formula (I)as described above, and their salts, solvate and physiologically functional derivatives.

The compounds of formula I and their pharmaceutically tolerated salts and physiologically functional derivatives represent an ideal drug for the treatment of disorders of lipid metabolism, in particular hyperlipidemia. The compounds of formula I can be used to influence the level of serum cholesterol, as well as for prevention and treatment arteriosclerotic manifestations.

Link is(I) can also be used in combination with other active substances.

The number of compounds according to formula (I), which is necessary to achieve the desired biological effect depends on a number of factors, such as specific compounds, the method of administration, type of application and the clinical condition of the patient. In General, the daily dose is in the range of 0.1-100 mg (mainly from 0.1 mg to 50 mg) per day per kilogram of body weight, such as 0.1-10 mg/kg/day. Tablets or capsules may, for example, contain from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically-tolerated salts of these quantitative data relate to the weight of ions of diphenylacetylene contained in the salt. For the prevention or therapy of the abovementioned conditions, the compounds according to formula (I) can be used alone, but preferably they are used with portable media in the form of pharmaceutical compositions. The carrier must, of course, be portable in the sense that it is compatible with other components of the composition and does not harm the health of the patient. The carrier may be solid or liquid, or both, and preferably together with the compound prepared in the form of individual doses, for example in the form of a tablet, which may contain from 0.05% to 95 wt.% the active substance. There may be other pharmaceutically active substances, including other joint is according to formula (I). The pharmaceutical compositions according to the invention can be obtained by one of the known pharmaceutical methods, which mainly consist in the fact that the component parts are mixed with pharmacologically tolerable carriers and/or auxiliary substances.

Pharmaceutical compositions related to the invention are those which are suitable for oral and peroral (for example sublingual) administration although the most suitable route of administration in each individual case depend on the type and severity of the condition and the type of each of the applied compounds of formula (I). To the field of the invention also include index dosage forms and index pharmaceutical form prolonged action. Preferred dosage forms, resistant to acid and gastric juice. Suitable resistant to gastric juice cover cover acetated cellulose, polyvinyl acetate phthalate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable for oral administration, the pharmaceutical compounds can be offered as individual units, such as capsules, pills, sucking tablets or pills, which in each case contain a certain number of compounds according to formula (I); as a powder or grain is Yat; as solution or suspension in an aqueous or nonaqueous liquid; or as an emulsion of oil-in-water" or "water in oil". These compositions can, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active substance and the carrier (which may consist of one or more parts) are in contact. Typically, the compositions have a uniform and homogeneous mixing of the active substance with a liquid and/or powdered solid carrier, after which the product, if necessary, is formed. For example, the tablet can get that powder or granules of the compound is pressed or molded, optionally with one or more additional components. Molded tablets can be obtained by tableting the compound in free-flowing form such as powder or granules, optionally mixed with a binder, a softening agent, an inert diluent and/or one (several) of surface-active/dispersing agent in a suitable device. Molded tablets can be obtained by molding the powdered compound moistened inert liquid diluent in a suitable device.

Pharmaceutical compositions suitable for peroral (sublingual) administration include sucking pill, which which may contain the compound according to formula (I) with a flavoring agent, normally sucrose and gum Arabic or Trianta, and lozenges, which contain the compound in an inert basis as gelatin and glycerol or sucrose and gum Arabic.

Other suitable active materials for combination drugs are all antidiabetic agents, which are named Red list 2001, Chapter 12. They can be combined with the invention compounds of formula I, first of all, for a synergistic improvement actions. The use of combinations of active substances may be either separate introduction of an active substance to a patient or in the form of a combined preparation, which contains several active substances in one pharmaceutical finished form.

Antidiabetic agents include insulin and derivatives of insulin, such as Lantus® or HMR 1964, derivatives of GLP-1, such as those published in the application WO 98/08871, filed by Novo Nordisk A/S, as well as orally active hypoglycemic active ingredients.

Hypoglycemic active ingredients for oral administration include mainly sulfonylurea, bigouden, meglitinide, oxadiazolidine preparations, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, agonists of GLP-1, potassium channel activators, such as those published applications WO 97/2265 and WO 99/03861 company Novo Nordisk A/S, insulinsensitizing substances, inhibitors of liver enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, modulators of absorption of glucose, compounds that alter fat metabolism, as antihyperlipidemics active substances and antilipidemic active ingredients, compounds which reduce the intake of food, agonists of PPAR and PXR to define against and agents acting on the ATP-dependent potassium channel of the beta cells.

In one form of execution of the invention the compounds of formula I are used in combination with an inhibitor of HMG-COA reductase, as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, tseriwastatina, rosuvastatin.

In one form of execution of the invention the compounds of formula I are used in combination with an inhibitor of the absorption of cholesterol, such as ezetimibe, tiqueside, pemaquid. In one form of execution of the invention the compounds of formula I are used in combination with an agonist of PPAR-gamma, as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.

In one form of execution of the invention the compounds of formula I are used in combination with an agonist of PPAR-alpha, as, for example, GW 9578, GW 7647.

In one form of execution of the invention the compounds of formula I are used in combination with a mixture of agonists, PPAR alpha/gamma, as, for example, GW-1536, AVE 8042, AVE 8134, AVE 0847.

the one form of execution of the invention the compounds of formula I are used in combination with vibrator, as, for example, fenofibrate, clofibrate, bezafibrat.

In one form of execution of the invention the compounds of formula I are used in combination with an MTP inhibitor, such as Bay 13-9952, BMS-201038, R-103757.

In one form of execution of the invention the compounds of formula I are used in combination with an inhibitor of the absorption of bile acids, as, for example, HMR 1453.

In one form of execution of the invention the compounds of formula I are used in combination with a CETP inhibitor, such as Bay 194789.

In one form of execution of the invention the compounds of formula I are used in combination with a polymeric bile acid adsorber, such as cholestyramine, Kolesova.

In one form of execution of the invention the compounds of formula I are used in combination with the inductor LDL-receptor, such as, for example, HMR1171, HMR1586.

In one form of execution of the invention the compounds of formula I are used in combination with an ACAT inhibitor, such as, for example, avasimibe.

In one form of execution of the invention the compounds of formula I are used in combination with an antioxidant, such as, for example, OPC-14117.

In one form of execution of the invention the compounds of formula I are used in combination with an inhibitor of lipoprotein lipase, as, for example, NO-1886.

In one form of execution of the invention the compounds of formula I are used in combination with an inhibitor of ATP-citrate-LiAZ as, for example, SB-204990.

In one form of execution of the invention the compounds of formula I are used in combination with an inhibitor of squalene synthetase, as, for example, BMS-188494.

In one form of execution of the invention the compounds of formula I is used in combination with an antagonist of lipoproteins, such as CI-1027 or nicotinic acid.

In one form of execution of the invention the compounds of formula I are used in combination with a lipase inhibitor, such as orlistat.

In one form of execution of the invention the compounds of formula I are used in combination with insulin.

In one form of execution of the invention the compounds of formula I are used in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide.

In one form of the invention the compounds of formula I are used in combination with biguanides, as, for example, Metformin.

In another form of the invention the compounds of formula I are used in combination with meglitinides, as, for example, Repaglinide.

In one form of the invention the compounds of formula I are used in combination with thiazolidinediones, as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds, published in the application WO 97/41097 submitted by Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-girasolereale is XI]phenyl]methyl]-2,4-thiazolidinedione.

In one form of the invention the compounds of formula I are used in combination with the inhibitor α-glucosidase, as, for example, miglitol or acarbose.

In one form of the invention the compounds of formula I are used in combination with the active substance acting on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glazed or Repaglinide.

In one form of the invention the compounds of formula I are used in combination with more than one of the previously mentioned compounds e.g. in combination with a sulfonylurea and Metformin, a sulfonylurea and acarbose, Repaglinide and Metformin, insulin and a sulfonylurea, insulin and Metformin, insulin and troglitazone, insulin and lovastatin, etc

In another form of execution of the invention the compounds of formula I are used in combination with CART agonists, NPY agonists, MC4 agonists, agonists of orexin, H3 agonists, TNF agonists, CRF agonists, CRF antagonists BP, agonists urocortin, agonists β3, agonists, MSH (melanocyte-stimulating hormone)agonists, CCK, inhibitors of reuptake of serotonin, mixed serotonin and noradrenergic compounds, 5HT agonists, agonists bombezin, antagonists Galanina, growth hormones, compounds that produce gormo the growth the TRH agonists, separating the protein 2 or 3 modulators, leptin agonists, DA agonists (parlodel, depressin), inhibitors of lipase/amylase, modulators of PPAR, RXR modulators or agonists TR-β.

In one form of the invention the other active ingredient is leptin.

In one form of the invention the other active ingredient is the dexamfetamine or amphetamine.

In one form of the invention the other active ingredient is fenfluramine or dexfenfluramine.

In another form of the invention the other active ingredient is subitramine.

In one form of the invention the other active ingredient is orlistat.

In one form of the invention the other active ingredient is mazindol or phentermine.

In one form of the invention the compounds of formula I are used in combination with ballast substances, mainly of insoluble dietary fiber, as, for example, Caromax®. Combination with Caromax®can occur in one final product or the separate introduction of the compounds of formula I and Caromax®. Caromax®can be served with food, as, for example, in bakery products and cereals muesli. The combination of compounds is ormula I Caromax ®is shown, along with the improvement actions, in particular, reduction of LDL-cholesterol (low density lipoprotein), compared to the individual active substances, and improved tolerability.

Assume that every suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances falls under the protection of the present invention.

Further, the subject invention are as stereoisomeric mixtures of formula I and the pure stereoisomers of the formula I, as well as diastereomeric mixture of formula I and the pure diastereomers. The separation of the mixture is carried out by chromatographic method.

Preferred are racemic and pure enantiomeric compounds of the formula I with the following structure:

Further, preferred compounds of formula I, where the remainder of L has the following value:

The subject of the invention is, further, a method of obtaining compounds of General formula I, characterized in that obtaining the compounds of formula I is similar to the following reaction scheme.

R4 means (C0-C30-alkylen, and Odie is or more C atoms of alkyl residue may be replaced by-O-, -(C=O)-, -CH=CH-, -C≡C, ((C1-C6)-alkyl)- or-NH-.

The alternative is linking from L-band through the ring A or ring C

The following examples serve more detailed explanation of the invention is not limited to the products described in the examples and forms of execution.

Example I

5-{4-[3-(3-hydroxy-3-phenylpropyl)-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}pentane acid-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide (1)

100 mg 5-bromopentanoate acid-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide and 70 mg of 1-(4-aminomethylphenol)-3-(3-hydroxy-3-phenylpropyl)-4-(4-methoxyphenyl)azetidin-2-dissolve it in 5 ml of dimethylformamide and heated for 2 to 3 hours under stirring to 80°C. After the reaction (monitoring by thin-layer chromatography (TLC) or HPLC-MS) the solvent is removed in vacuum and the residue is cleaned using chromatography. So get the product of 1 molecular weight 929,24 (C55H68N4O7S); MS(FAB): 929 (M+H+).

Example II

[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide and 4-[1-(4-forfinal)-3-(3-hydroxy-3-phenylpropyl)-4-oxoazetidin-2-yl]benzylamine Huck is addicabadaway acid (8)

a) 1-(2-oxo-4-phenyloxazolidine-3-yl)-5-phenylpentane-1,5-dione (2)

10 g benzoylamino acid and 12.5 ml of triethylamine are dissolved in 55 ml of dichloromethane. After 5 min at room temperature for 30 min add to 6.2 ml pivaloyloxy and stirred for 2 hours Then added to 5.9 g of 4-phenyl-oxazolidin-2-it in 6 ml of dimethylformamide and 0.9 g of 4-(dimethylamino)pyridine. Heat about 7 h under reflux (TLC-control). After the reaction was added 15 ml of 2-n sulfuric acid, stirred for a short time and then the phases are separated. The organic phase is washed with 5% bicarbonate solution, after drying, concentration and recrystallization from a mixture of ethyl acetate/n-heptane receive the product with the molecular weight 337,4 (C20H19NO4); MS (DCI+): 338 (M+H+). When using optically active/enriched enantiomeric forms of 4-phenyl-oxazolidin-2-get it the same way optically active/enriched enantiomeric forms of the product 2.

b) 3-(5-hydroxy-5-phenylpentane)-4-phenyl-oxazolidin-2-he (3)

To a solution of 1.5 ml of complex Bordetella in 25 ml dichloromethane is slowly added over about 3 hours in an argon atmosphere at a temperature between 0° -5°C 5 g of 1-(2-oxo-4-phenyl-oxazolidin-3-yl)-5-phenylpentane-1,5-dione in 20 ml of dichloromethane. Stirred for 2 h at the same temperature and con the check by thin-layer chromatography. After becoming added at 0°C 2 ml of methanol and 1.5 ml of 35% hydrogen peroxide solution and 1.1 ml of 3 N. sulfuric acid and stirred for 15 min at room temperature. After phase separation the organic phase is washed successively: 2 N. sulfuric acid, 5% solution of sodium bisulfite, 10% sodium chloride solution and then dried and concentrated. After chromatography (SiO2, ethyl acetate/n-heptane=1:1) receive the product with the molecular weight 339,4 (C20H21NO4); MS (DCI+): 322 (M+H+-H2O); (ESI+): 403 (M+Na++CH3CN), 362 (M+Na+). Adding to the reaction mixture of optically active 1-methyl-3,3-divanillytetrahydrofuran[1,2-c][1,3,2]oxanabol (S or R, 0.75 ml) at a temperature of from 0°-5°C before the introduction of 1-(2-oxo-4-phenyloxazolidine-3-yl)-5-phenylpentane-1,5-dione in a similar way we obtain the product 3 in the form of enriched diastereomers.

c) 4-[1-(4-forgenerating)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-5-phenyl-5-trimethylsilylmethyl]benzonitrile (4)

of 3.3 g of 3-(5-hydroxy-5-phenylpentane)-4-phenyloxazolidine-2-it 3,93 g of 4-[(4-ftorpirimidinu)methyl]benzonitrile dissolved in 55 ml of dichloromethane, cooled to -10°C and slowly mixed with 8.5 ml of diisopropylethylamine. Within 30 minutes, added with 5.3 ml of chlorotrimethylsilane so that the temperature remained below 5°. After one hour, cooled to -30°C and add 1.1 ml of titanium tetrachloride at a temperature below -25°C and then stirred overnight at this temperature. After becoming added dropwise 4 ml of ice-cold vinegar at -25°C, then stirred for 15 min, add at 0°C 50 ml of 7% tartaric acid and stirred for 1 h, then add 25 ml of 20% solution of sodium bisulfite is added and stirred for a further 45 minutes After separation of the phases the organic phase is washed with about 40 ml of water, dried and concentrated to about 15 ml and Then added to 2.7 ml of batrineteasinguratatea and heated for 30 min under reflux. After cooling to room temperature, concentrate and after crystallization of the residue from a mixture of ethyl acetate/n-heptane receive the product with the molecular weight 635,8 (C37H38FN3About4Si); MS (ESI+): 636 (M+H+).

d) 4-[1-(4-forfinal)-3-(3-hydroxy-3-phenylpropyl)-4-oxoazetidin-2-yl]benzonitrile (5)

2.7 g of 4-[1-(4-forgenerating)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-5-phenyl-5-trimethylsilylmethyl]benzonitrile heated in 30 ml of tert-butylmethylether with 1.6 ml of batrineteasinguratatea and 0.2 g of three-hydrate of tetrabutylammonium 3 h under reflux. After maturation during the night add 0.2 ml of ice-cold vinegar, stirred for 15 min and strongly focus is. To this is added 15 ml of a mixture of isopropanol/2 N. sulfuric acid = 10:1 and stirred for 1 h at room temperature. After treated with a small amount of solid sodium bicarbonate, again strongly concentrate, collect the residue in ethyl acetate and washed with water. The remainder of the dried organic phase is cleaned by filtering through a column (SiO2, ethyl acetate/n-heptane=1:1). Get the product with the molecular weight 400,5 (C25H21FN2About2); MS (DCI+): 401 (M+H+), 383 (M+H+-H2O).

e) 4-(4-aminomethylphenol)-1-(4-forfinal)-3-(3-hydroxy-3-phenylpropyl)azetidin-2-he (6)

930 mg of 4-[1-(4-forfinal)-3-(3-hydroxy-3-phenylpropyl)-4-oxoazetidin-2-yl]benzonitrile dissolved in 100 ml of ethanol, mixed with 4 ml of concentrated ammonia and hydronaut 20 h at room temperature and 20 bar of hydrogen using a Nickel of Renee. Sucked off from the catalyst, concentrated in vacuo and obtained after chromatography (SiO2, dichloromethane/methanol=10:1) product with a molecular weight 404,5 (C25H25FN2About2); MS (DCI+): 405 (M+H+), 387 (M+H+-H2O).

f) 5-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]pentane acid (7)

2 g of 5-(3-AMINOPHENYL)-3-butyl-7-dimethylamino-3-ethyl-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol, 3,4 g hexadecanoic acid, 1,g dicyclohexylcarbodiimide and 640 mg benzotriazol-1-ol is stirred in 80 ml of tetrahydrofuran over night at room temperature. Concentrate, gather the remnant with ethyl acetate, filtered from excess urea and washed with water. The remainder of the dried organic phase is cleaned by filtering on a column (SiO2, dichloromethane/methanol=20:1). Get the product with the molecular weight 558,7 (C30H42N2O6S); MS (ESI+): 559 (M+H+).

g) [3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide and 4-[1-(4-forfinal)-3-(3-hydroxy-3-phenylpropyl)-4-oxoazetidin-2-yl]benzylamine hexadecanoic acid (8)

83 mg of 4-(4-aminomethylphenol)-1-(4-forfinal)-3-(3-hydroxy-3-phenylpropyl)azetidin-2-it, 115 mg of 5-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]pentanol acid, 45 mg of dicyclohexylcarbodiimide and 35 mg benzotriazol-1-ol is stirred in 5 ml of tetrahydrofuran over night at room temperature. Concentrated in vacuo and after chromatography (SiO2, dichloromethane/methanol=20:1) receive a product with a melting point of 150°C and molecular weight 945,2 (C55H65FN4O7S); MS (ESI+): 945 (M+H+).

Example III

[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide and 4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzimidazolecarbamic acid (12)

a) 4-[5-(4-forfinal)-1-(4-forgenerating)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-5-trimethylsilylmethyl]benzonitrile (9)

Obtain analogously to example II using 3-[5-(4-forfinal)-5-hydroxypentanal]-4-phenyloxazolidine-2-it.

The product with the molecular weight 653,8 (C37H37F2N3About4Si); MS (ESI+): 654 (M+H+).

b) 4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzonitrile (10)

Obtain analogously to example II, using 4-[5-(4-forfinal)-1-(4-forgenerating)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-5-trimethylsilylmethyl]benzonitrile; the product with the molecular weight 418,5 (C25H20F2N2O2); MS (ESI+):419(M+H+).

c) 4-(4-aminomethylphenol)-1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]azetidin-2-he (11)

Obtain analogously to example II, using 4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzonitrile.

The product with the molecular weight 422,5 (C25H24F2N2O2); MS (ESI+): 423 (M+H+).

d) [3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide and 4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl}benzylated hexadecanoic acid (12)

Obtain analogously to example II; the product with the molecular weight 963,2 (C55H64F2 N4About7S); MS (ESI+): 963 (M+H+).

Example V

[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide and 4-[3-(3-hydroxy-3-phenylpropyl)-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamine hexadecanoic acid (15)

Obtain analogously to example III, on the basis of 1-(4-aminomethylphenol)-3-(3-hydroxy-3-phenylpropyl)-4-(4-methoxyphenyl)azetidin-2-it.

The product with the molecular weight 957,2 (C56H68N4About8S); MS(ESI+): 957 (M+H+).

Example VI

[2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]methoxy}ethoxy)ethoxy]-[N-{4-[1-(4-forfinal)-3-(3-hydroxy-3-phenylpropyl)-4-oxoazetidin-2-yl]benzyl}]-ndimethylacetamide (16)

Obtain analogously to example II, on the basis of 83 mg of 4-(4-aminomethylphenol)-1-(4-forfinal)-3-(3-hydroxy-3-phenylpropyl)azetidin-2-she and 130 mg of [2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]methoxy}ethoxy)ethoxy] acetic the acid.

Chromatography: SiO2, dichloromethane/methanol=20:1; the product with a melting point of 120°C and molecular weight 1021,3 (C57H67FN4O10S); MS (ESI+): 1021 (M+H+).

Example VII

(3-butyl-3-ethyl-5-[3-(2-{2-[(4-{1-(-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)methoxy]ethoxy}acetylamino)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (18)

a) (2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]methoxy}ethoxy)acetic acid (17)

To 965 mg of a solution of 10 g dioxoanthracene acid, 188 mg of hydroxybenzotriazole and 287 mg of dicyclohexylcarbodiimide in 10 ml of tetrahydrofuran (THF) is added dropwise within 2 h of 500 mg 5-(3-amino-phenyl)-3-butyl-7-dimethylamino-3-ethyl-1,1-dioxo-2,3,4,5-tetrahydro-1H-1-benzo[b]thiepin-4-ol in 8 ml of THF. Stirred at room temperature for 12 hours the Reaction solution is concentrated and collected 2 N. hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, concentrated and cleaned using HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1 % of triperoxonane acid)/acetonitrile (0.1% of triperoxonane acid)=80/20->10/90). Get the product 17.

C30H41N2O8S1(590,74); MS (ESI): 592 (M+H).

b) (3-butyl-3-ethyl-5-[3-(2-{2-[(4-{1-(4-forfinal)-3-[3-(4-forefeel)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)methoxy]ethoxy}acetylamino)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)-dimethylamine; triptorelin (18)

A solution of 100 mg 4-(4-aminomethylphenol)-1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]azetidin-2-it, 209 mg (2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-Tetra the DRO-1H-benzo[b]thiepin-5-yl)-phenylcarbamoyl]methoxy}ethoxy)acetic acid, 93 μl of diisopropylcarbodiimide, 65 mg of hydroxybenzotriazole in 2 ml of methylene chloride was stirred for 12 h at room temperature. Add water and extracted with methylene chloride. The organic phase is dried over magnesium sulfate, concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1 % of triperoxonane acid)/acetonitrile (0.1% of triperoxonane acid)=80/20->10/90). Get the product 18.

C57H63F5N4O11S1(1109,23); MS (ESI): 977 (M+H-H2O).

Analogously to example VII receive the following examples (VIII-XXIV):

Example VIII

(3-butyl-3-ethyl-5-[3-(2-{2-[(3-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)methoxy]ethoxy}acetylamino)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (19)

C57H65F5N4About11S1(1109,23); MS (ESI): 977 (M+H-H2O).

Example IX

3-butyl-3-ethyl-5-{3-[2-(2-{2-[(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl}benzylcarbamoyl)methoxy]ethoxy}ethoxy)acetylamino]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (21)

a) [2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)forcarb mail]methoxy}ethoxy)ethoxy]acetic acid (20)

C32H46N2O3S1(634,3); MS (ESI): 635 (M+H).

b) (3-butyl-3-ethyl-5-{3-[2-(2-{2-[(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)methoxy]ethoxy}ethoxy)acetylamino]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)-dimethylammonio; triptorelin (21)

C59H69F5N4O12S1(1153,28); MS (ESI): 1039 (M+H).

Example X

(3-butyl-3-ethyl-5-{3-[2-(2-{2-[(3-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)methoxy]ethoxy}ethoxy)acetylamino]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (22)

C59H69F5N4O12S1(1153,28); MS (ESI): 1040 (M + H).

Example XI

(3-butyl-3-ethyl-5-{3-[11-(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)undecanoyl]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (24)

a) 11-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]undecanoate acid (23)

C36H54N2O6S1(642,91); MS (ESI): 643 (M + H).

b) (3-butyl-3-ethyl-5-{3-[11-(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)undecanoyl]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (24)

C63H77F5N4O9S1(1161,39); MS (ESI): 1047 (M+H).

Example XII

(3-butyl-3-ethyl-5-{3-[11-(3-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)undecanoyl]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (25)

C63H77F5N4O9S1(1161,39); MS (ESI): 1047 (M+H).

Example XXI

{3-butyl-3-ethyl-5-{3-[2-(2-{2-[(4-[3-(3-hydroxy-3-phenylpropyl)-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl)methoxy]ethoxy}ethoxy)acetylamino]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (38)

C60H73F3N4O13S1(1147,33); MS (ESI): 1033 (M+H).

Example XXII

{3-butyl-3-ethyl-5-[3-(3-{2-[2-(2-{2-[2-(3-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}

propionamido)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (2)

a) tert-butyl ether 3-[2-(2-{2-[2-(2-tert-butoxycarbonylamino)ethoxy]ethoxy}ethoxy)ethoxy]propionic acid (39)

To a solution of 91 tetraethyleneglycol in 250 ml of tetrahydrofuran, add 0.4 g of sodium and stirred at room temperature. When the sodium has dissolved, add 145 ml of tert-butyl acrylate. Stirred for 12 hours the Reaction solution is neutralized with ammonium chloride, concentrated and collected in an aqueous solution of sodium chloride and extracted with ethyl acetate. The organic phase concentrated. The remainder is 39.

C22H42O9(450,57); MS (ESI): 339 (M + 3*H - 2* t-Bu).

b)3-[2-(2-{2-[2-(2-carboxy-ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionic acid (40)

A solution of tert-butyl ester 3-[2-(2-{2-[2-(2-tert-butoxycarbonylamino)ethoxy]ethoxy}ethoxy)ethoxy]propionic acid 24 in 50 ml of methylene chloride is stirred with 50 ml triperoxonane acid for 2 h and concentrated. The remainder collect 1 N. hydrochloric acid and extracted with methylene chloride. The organic phases are concentrated and get 40.

C14H26O9(338,36); MS (ESI): 339 (M+H).

c) 3-(2-{2-[2-(2-{2-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-[tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)propionic acid (41)

Synthesis is carried out anal is Gino 17.

C39H60N2O11S1(750,97); MS (ESI): 751 (M+H).

d) {3-butyl-3-ethyl-5-[3-(3-{2-[2-(2-{2-[2-(3-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}

propionamido)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (42)

C65H81F5N4O14S1(1269,44); MS (ESI): 1155 (M+H).

Example XXIII

[3-butyl-3-ethyl-5-(3-{3-[2-(2-{2-[2-(2-{2-[2-{3-[1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl]benzylcarbamoyl)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy) ethoxy]propionamide}phenyl)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl]dimethylamine; triptorelin (46)

a) tert-butyl ether 3-(2-{2-[2-(2-{2-[2-(2-tert-butoxycarbonylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}-ethoxy)propionic acid (43)

The synthesis proceeds in a similar 39.

C26H50O11(538,68); MS (ESI): 427 (M+3*H-2*t-Bu).

b) 3-(2-{2-[2-(2-{2-[2-(2-carboxymethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)-propionic acid (44)

Synthesis is carried out analogously to 40.

C18H34O11(426,47); MS (ESI): 427 (M+H).

c) 3-{2-[2-(2-{2-[2-(2-{2-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-d is oxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]-ethoxy}propionic acid (45)

The synthesis proceeds in a similar 17.

C43H66N2O3S1(839,09); MS (ESI): 840 (M + H).

d) [3-butyl-3-ethyl-5-(3-{3-[2-(2-{2-[2-(2-{2-[2-{3-[1-(4-forfinal)-3-[3-(4-forefeel)-3-hydroxypropyl]-4-oxoazetidin-2-yl]benzylcarbamoyl}ethoxy]ethoxy}ethoxy)ethoxy] ethoxy}ethoxy)ethoxy]propionamide}phenyl)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl]-dimethylamine; triptorelin (46)

C69H89F5N4O16S1(1357,55); MS (ESI): 1243 (M + H).

Example XXIV

[3-butyl-3-ethyl-5-(3-{3-[2-(2-{2-[2-({2-{2-[2-(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)ethoxy)ethoxy]ethoxy}ethoxy)ethoxy] propionamide}phenyl)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl]dimethylamine; triptorelin (47)

C65H81F5N4O14S1(1269,44); MS (ESI): 1243 (M+H).

Example XXV

(3-butyl-3-ethyl-5-{3-[8-(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylamino)octanoylthio]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (50)

a) 7-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenylcarbamoyl]heptane acid (48)

Synthesis is carried out analogously 17.

C33H48N2O6S1(600,82); MS (ESI): 601 (M + H).

b) [3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide methoxyethylamine octadecenoic acid (49)

To a solution of 550 mg of 7-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1-benzo[b]thiepin-5-yl) phenylcarbamoyl]heptane acid, 311 μl of diisopropylcarbodiimide, 272 mg of hydroxybenzotriazole in 10 ml of methylene chloride added at room temperature a solution of 223 mg of O,N-dimethylhydroxylamine and 391 μl of diisopropylethylamine in 5 ml of acetonitrile and stirred for 12 h. The reaction solution is concentrated and cleaned by HPLC (Merck-Hibar-Lichrospher 100-RP-18, water (0.1% of triperoxonane acid)/acetonitrile (0.1% of triperoxonane acid)=80/20->10/90).

C35H53N3O6S1(643,89); MS (ESI): 644 (M+H).

c) (3-butyl-3-ethyl-5-{3-[8-(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl}benzoylamino)octanoylthio]phenyl}-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (50)

To a solution of 160 mg octadecanoate acid-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]amide of methoxyethylamine 34 in 1 ml of tetrahydrofuran stirred into the ri -78° C is 0.22 ml of 1 M solution of diisobutylaluminium in hexane and stirred for 30 min. The reaction solution is mixed with water and extracted with methylene chloride. Concentrate and collect 3 ml of a mixture of tetrahydrofuran and methanol (1/1, 1% acetic acid). To this add 131 mg of 4-(3-aminomethylphenol)-1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]azetidin-2-she and 58 mg cyanoborohydride sodium. After 12 h, the reaction mixture is mixed with water, extracted with methylene chloride and the organic phase concentrated. The residue is cleaned by HPLC (Knauer Eurospher-100-10-C18, water (0.1% of triperoxonane acid)/acetonitrile (0.1% of triperoxonane acid)=80/20->10/90).

C58H72F2N4O6S1(991,30); MS (ESI): 991 (M+H).

Example XXVI

{3-butyl-3-ethyl-5-[3-(2-{2-[2-(3-{1-(4-forfinal)-3-[3-{4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl) benzylamino)ethoxy]ethoxy}acetylamino)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (52)

a) 2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl) phenylcarbamoyl]methoxy}ethoxy)-N-methoxy-N-methyl-ndimethylacetamide (51)

Synthesis 49 similarly, on the basis of 17.

C32H47N3About8S1(633,81); MS (ESI): 634 (M+H).

b) {3-butyl-3-ethyl-5-[3-(2-{2-[2-(3-{1-(4-forfinal)-3-[3-(4-FPO is phenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl)-benzylamino)ethoxy]ethoxy}acetylamino)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylammonio; triptorelin (52)

Synthesis analogously to 50.

C57H67F5N4O10S1(1095,25); MS (ESI): 982 (M + H).

Example XXVII

{3-butyl-3-ethyl-5-[3-(2-{2-[2-(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl) benzylamino)ethoxy]ethoxy}acetylamino)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (53)

Synthesis analogously to 50.

C57H67F5N4O10S1(1095,25); MS (ESI): 982 (M + H).

Example XXVIII

{3-butyl-3-ethyl-5-[3-(2-{2-[(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxy-propyl]-4-oxoazetidin-2-yl) benzylcarbamoyl)methoxy]ethoxy}ethylamino)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (58)

a) {2-[(methoxymethanol)methoxy]ethoxy}acetic acid (54)

To a solution of 10 g dioxoanthracene acid, 13 ml of diisopropylcarbodiimide, 11.4 g of hydroxybenzotriazole in 70 ml of methylene chloride add a solution of 5.5 g O N-dimethylhydroxylamine hydrochloride and 9.6 ml of diisopropylethylamine in 50 ml of acetonitrile and 40 ml of DMF and stirred for 12 hours, the Reaction solution is concentrated and cleaned using chromatography on silica gel (ethyl acetate/heptane/methanol/acetic acid=8/10/1/1->0/0/10/1).

C8H19N1About4(221,21); MS (ESI): 222(M+ H).

b) tert-butyl ether {2-[(methoxymethanol)methoxy]ethoxy}acetic acid (55)

To a solution of 2 g of {2-[(methoxymethanol)methoxy]ethoxy}acetic acid 39 in 20 ml of methylene chloride add 1.3 ml of thionyl chloride and stirred for 1 h at 60°C. After addition of 1.3 ml of tert-butanol is stirred and following 2 h at room temperature. Mixed with water, extracted with methylene chloride, concentrated and receive 55.

C12H23N1O6(277,32); MS(ESI): 222 (M+2*H-tert-butyl).

c) tert-butyl ether (2-{2-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylamino]ethoxy}ethoxy)acetic acid (56)

Synthesis analogously to 50, based on 55 and 5-(3-AMINOPHENYL)-3-butyl-7-dimethylamino-3-ethyl-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol.

C34H52N2O7S1(632,87); MS (ESI): 577 (M+2*H-tert-Bu).

d) (3-butyl-5-{3-[2-(2-carboxymethoxy-ethoxy)ethylamino] phenyl}3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (57)

A solution of 90 mg of tert-butyl methyl ether (2-{2-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylamino]ethoxy}ethoxy)acetic acid in 1 ml of methylene chloride is stirred for 2 h with 1 ml of triperoxonane the th acid and concentrated. The product is cleaned by HPLC (Knauer Eurospher-100-10-C18, water (0.1% of triperoxonane acid)/acetonitrile (0.1% of triperoxonane acid) = 80/20->10/90).

C30H44N2O7S1(576,76); MS(ESI): 577 (M+H).

e) {3-butyl-3-ethyl-5-[3-(2-{2-[(4-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl) benzylcarbamoyl)methoxy]ethoxy}ethylamino)phenyl]-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (58)

To a solution of 40 mg of the compound (2-{2-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylamino]ethoxy}ethoxy)acetic acid with triperoxonane acid, 37 μl of diisopropylcarbodiimide, 26 mg of hydroxybenzotriazole, 40 μl of triethylamine in 2 ml of dimethylformamide added 55 mg of 4-(4-aminomethylphenol)-1-(4-forfinal)-3-[3-(4-fluorescent-phenyl)-3-hydroxypropyl]azetidin-2 to it and stirred for 12 hours, the Reaction solution is concentrated and separated by HPLC (Merck-Hibar-Lichrospher 100-RP-18, water (0.1 % of triperoxonane acid)/acetonitrile (0.1% of triperoxonane acid)=80/20->10/90).

C57H67F5N4O10S1(1095,22); MS(ESI): 981 (M+H).

Example XXIX

{3-butyl-3-ethyl-5-[3-(2-{2-[(3-{1-(4-forfinal)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-oxoazetidin-2-yl)benzylcarbamoyl)methoxy]ethoxy}ethylamino)phenyl]-4-g is droxi-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-7-yl)dimethylamine; triptorelin (59)

Synthesis analogously 58.

C57H67F5N4O10S1(1095,22); MS(ESI): 981 (M+H).

Example XXX

2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl) phenylcarbamoyl]methoxy}ethoxy)-N-{4-[3-[3-(4-forfinal)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl] benzyl}ndimethylacetamide (65)

a) 3-[5-(tert-butyldimethylsilyloxy)-5-(4-forfinal)pentanoyl]-4-phenyloxazolidine-2-he (60)

27 g of 3-[5-(4-forfinal)-5-hydroxy-pentanoyl]-4-phenyloxazolidine-2-dissolve it with 13.6 g of tert-butyldimethylsilyloxy and 10.2 g of imidazole in 36 ml of dimethylformamide and stirred for 90 min at 60°C. After the reaction mixture is dissolved in ether, acetic acid and twice extracted by shaking with water. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. Receive 3-[5-(tert-butyldimethylsilyloxy)-5-(4-forfinal)pentanoyl]-4-phenyloxazolidine-2-he has a molecular weight of 471,65 (C26H34FNO4Si);

MS (ESI): 340,28 (MH+-HOSi(CH3)2C(CH3)3).

b) 4-[5-(tert-butyldimethylsilyloxy)-5-(4-forfinal)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamine]benzonitrile (61)

16.2 g of 3-[5-(tert-butyldimethylsilyloxy)-5-(4-forfinal)pentanoyl]-4-phenyloxazolidine-2-it is dissolved in 350 m is dichloromethane. The solution is mixed with 19.8 ml of base Hunga and 10,14 g of 4-[(4-methoxybenzylamine)methyl]benzonitrile and cooled to -10°C. To the cooled solution was added charged 8.52 ml trimethylsilyltriflate and stirred for 30 min at -10°C. the Solution is cooled to -30°C and add 44 ml of titanium tetrachloride. The reaction mixture is stirred for 2 hours at a temperature of from -30 to -40°C. Then the solution is heated to room temperature, washed reaction solution successively with 200 ml of 2 N. sulfuric acid, 300 ml of 20%aqueous solution of sodium hydrosulphate and a saturated solution of salt. The organic phase is dried over magnesium sulfate, concentrated in vacuo and the residue cleaned over silica gel with a mixture of n-heptane/ether acetic acid = 3/1. Receive 4-[5-(tert-butyldimethylsilyloxy)-5-(4-forfinal)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamine]benzonitrile molecular weight 707,93 (C41H46FN3O5Si);

MS(ESI): 590,51 (MH+-C7H5N2).

c) 4-[3-[3-(tert-butyldimethylsilyloxy)-3-(4-forfinal)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (62)

of 13.2 g of 4-[5-(tert-butyldimethylsilyloxy)-5-(4-forfinal)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamine]benzonitrile dissolved in 380 ml of methyl tert-butyl ether, is mixed with 18.6 ml N,O-bis(trimethylsilyl)-ndimethylacetamide and 1.86 ml-1 solution of tetrabutylammonium in tetrahydrofuran and stirred for 2 h at room temperature. After the reaction, add 10 ml of acetic acid, concentrate the reaction mixture under vacuum and clean the residue over silica gel with a mixture of toluene/ether acetic acid = 50/1. Receive 4-[3-[3-(tert-butyldimethylsilyloxy)-3-(4-forfinal)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile molecular weight 544,75 (C32H37FN2O3Si); MS (ESI): 545,56 (M+H+).

d) 4-[3-[3-(4-forfinal)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (63)

3.5 g of 4-[3-[3-(tert-butyldimethylsilyloxy)-3-(4-forfinal)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile dissolved in 65 ml of tetrahydrofuran, mixed with 0,74 ml of acetic acid and 8,03 ml of 1 M solution of tetrabutylammonium in tetrahydrofuran and stirred for 2 h at room temperature. After that add 4,82 ml of tetrabutylammonium and stirred for 3 h at the temperature of the back of the fridge. The cooled reaction mixture was concentrated in vacuo and the residue is cleaned using chromatography over silica gel with a mixture of n-heptane/ether acetic acid = 2/1. Receive 4-[3-[3-(4-forfinal)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile molecular weight 430,48 (C26H23FN2O3); MS(ESI): 431,24 (M+H+).

e) 1-(4-aminomethylphenol)-3-[3-(4-forfinal)-3-hydroxy-propyl]-4-(4-methoxyphenyl)azetidin-2-he(64)

1.22 g of 4-[3-[3-(4-fluoro-phenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile dissolved in 90 ml of ethanol, mixed with 10 ml of concentrated ammonia solution and the excess of Nickel Raney and stirred for 8 h at 60°C and hydrogen pressure of 10 bar. The reaction mixture is cooled overnight to room temperature; the next day is separated from the catalyst, the filtrate was concentrated in vacuo and the residue is cleaned using chromatography over silica gel with a mixture of dichloromethane/methanol/aqueous ammonia = 10/1/0,1. Get 1-(4-aminomethylphenol)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-it has a molecular weight of 434,51 (C26H27FN2O3);

MS(ESI): 418,2 (MH+-NH3).

f) 2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]methoxy}ethoxy)-N-{4-[3-[3-(4-forfinal)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzyl}ndimethylacetamide (65)

140 mg of (2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]methoxy}ethoxy)acetic acid (17) and 100 mg of 1-(4-aminomethylphenol)-3-[3-(4-forfinal)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-it is dissolved at room temperature in 5 ml of dimethylformamide, mixed with 35 mg of 1-hydroxy-benzotriazole and 45 mg of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbody the IDA and stirred for 6 h at room temperature. The reaction mixture was concentrated in vacuo. The residue is mixed with dichloromethane, extracted twice with water by shaking and once with a saturated solution of sodium chloride; the organic extract is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was cleaned using chromatography (RP18; dichloromethane/methanol = 96/4 after dichloromethane/methanol 92/8 for 25 min). Receive product with a melting point 116-125°C. Molecular weight 1007,24 (C56H67FN4O10S); MS (ESI): 1008,53 (M+H+).

Example XXXI

N-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]-2-{2-[2-({4-[3-[3-(4-forefeel)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl)methoxy)ethoxy]ethoxy}ndimethylacetamide (66)

The compound from example 3 are given as the compound of example 2, with the difference that instead of (17) was used [2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]methoxy}ethoxy)ethoxy]acetic acid (20).

Molecular weight 1051,29 (C58H71FN4O11S); MS (ESI): 1052,51 (M+H+).

The action related to the invention of compounds of formula I were tested methods described below.

The influence of cholesterol absorption + selection3H-taurocholate KIS is the notes through fecal excretions of mice rats or hamsters

Mouse strain NMRI, Wistar rats or Golden Syrian hamsters (n=4-6) were kept on a standard diet (firm Altromin, Lag (Lippe)) in the cells. In the afternoon, before the introduction of a radioactive label (14C-cholesterol) animals not fed and taught to the grate.

Additionally for 24 hours before oral intake of the test food (14C-cholesterol in Intralipid®20, Pharmacia-decision Upjohn); animals were marked3H-TCA (taurocholic acid) (for example, from 1 µci (microcurie) on mouse up to 5 µci per rat).

Test the absorption of cholesterol: 0.25 ml/mouse Intralipid®20 (Pharmacia-decision Upjohn) (injection of 0.25 µci14C-cholesterol in 0.1 mg of cholesterol) is administered orally using gastric zonder substances are separated in a mixture: of 0.5%methylcellulose (Sigma)/5%solutol (BASF, Ludwigshafen) or rebuff a suitable binder. The amount of admission test substance is 0.5 ml/mouse. The test substance is applied directly to the test meal (intralipid tagged with14C-cholesterol) test for cholesterol absorption).

Feces collected after 24 h: fecal excretion14C-cholesterol and3H taurocholic acid (TCA) are defined in 24 hours

The liver is removed, homogenized, and an aliquot of burned oximate (model 307, Packard) to determine p is Ignatovo/ingested amount 14C-cholesterol.

Evaluation.

Samples of feces.

Determine the total weight, fill with water up to a certain amount, then homogenized, aliquot is dried and burned in oximate (model 307, Packard burning radioactively labelled samples): the quantity of radioactive3H - H2O and14C - CO2calculated exactly on the selected number of3H-taurocholic acid or14C-cholesterol (dohistory method). The value of the ED200is interpolated along the curve of action of the dose on the dose, which doubles the allocation of TCA or cholesterol in relation to simultaneously treated control group.

Liver samples.

Seized a number of14C-cholesterol in the liver is recalculated on the applied dose. The value of the ED50is interpolated from the curve of action of the dose on the dose that is half (50%) reduces the accumulation of14C-cholesterol compared to the control group.

The following values ED50confirm the activity of the invention compounds of formula I

Example NED50(liver) [mg/mouse]
II0.01
III0.03
VIII0.003
XXV0.01
XXXI0.1

From the persons should the compounds of formula I have a very good ability to reduce cholesterol.

The ability to suction.

The capacity for absorption of the compounds of formula I were tested on the model of Caco-cells (A.R. Hilgers and others, Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa, Pharm. Res. 1990, 7, 902).

From these measurements it follows that the invention concerns the compounds of formula I find significantly less absorbability as compared with the compounds described in the prior art.

Standard structureExample XII
effective separation factor of Papp[cm/s] (respectively, publ. Hilgers)4,88x10-063,67x10-09
Estimated resorption person 100%<1%

Standard structure:

ezetimibe

1. Derivatives of diphenylacetylene formula I

where R1, R2, R3, R4 independently from each other mean (C0-C30-alkylene-L, and one or more C-atoms alkalinous residue can be substituted by-O-, -(C=O)- or-NH-; in addition, R1-R6 can represent H, F;

L represents

R7 is methyl, ethyl, is ropel, butyl;

R8 - HE;

R9 is methyl, ethyl, propyl, butyl;

R10 is methyl, ethyl, propyl, butyl;

and there is always at least one of the residues R1-R4 must be set (With0-C30-alkylene-L, and one or more C-atoms alkalinous residue can be substituted by-O-, -(C=O)- or-NH-, and their pharmaceutically tolerated salts.

2. The compounds of formula I according to claim 1, characterized in that the mean of R1, R2, R3, R4 independently from each other -(CH2)0-1-NH-(C=O)0-1-(C3-C25-alkylene-(C=O)0-1-NH-L, and one or more C-atoms alkalinous residue can be substituted by O-atoms; in addition, R1-R6 can represent H, F;

L represents

R7 is methyl, ethyl, propyl, butyl;

R8 - HE;

R9 is methyl, ethyl, propyl, butyl;

R10 is methyl, ethyl, propyl, butyl;

where one of the residues R1 or R3 has the value -(CH2)0-1-NH-(C=O)0-1-(C3-C25-alkylene-(C=O)0-1-NH-L, and one or more C-atoms alkalinous residue can be replaced by O atoms, and their pharmaceutically tolerated salts.

3. Drug, showing lipid-lowering action, containing as active substance one or more compounds according to claim 1 or 2, and pharmaceutically usable nose is tel.

4. Compounds according to claim 1 or 2, showing the hypolipidemic action, for use as a drug for the treatment of lipid metabolism disorders.

5. The use of compounds according to claim 1 or 2 to obtain drugs for treatment of disorders of lipid metabolism.

6. The use according to claim 5 to obtain drugs for the treatment of hyperlipidemia.

7. The use according to claim 5 for receiving drugs to reduce serum cholesterol.



 

Same patents:

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

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

28 cl, 10 tbl, 16 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino}-3,3-diphenylpropanoyl}-2-pyrrolidine carboxamide maleate of the formula (1): . Also, invention relates to a method for preparing this compound by interaction of free compound of the formula (1) with maleic acid in the presence of organic solvent. This salt can be used as thrombin inhibitor.

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

4 cl, 2 tbl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

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

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry of natural compounds, medicine.

SUBSTANCE: invention relates to new taxanes with carbonate substitute at C7 of the general formula (I) given in the invention description wherein R2 means benzoyloxy group; R7 means -COO; R9 means -CO; R10 means -OH; R14 means hydrogen atom (H); X3 means (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom; X5 means -COX10, -COOX10 wherein X10 means (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom, and Ac means acetyl. Proposed compounds possess an anti-tumor activity.

EFFECT: valuable medicinal properties of compounds.

61 cl, 1 tbl, 5 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to derivatives of taxane of the general formula (I):

wherein R2 means acyloxy-group; R7 means hydroxy-group; R9 means keto-group; R10 means carbonate; R14 means hydrogen atom; X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted optionally with nitro-group or 5-6-membered heteroaromatic group comprising heteroatoms taken among oxygen (O), nitrogen (N) or sulfur (S) atoms; X5 means -C(O)X10, -C(O)OX10 or -CONHX10 wherein X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl, furyl, pyridyl or thienyl; Ac means acetyl. Also, invention describes a pharmaceutical composition based on taxanes and a method for inhibition of a tumor growth.

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

98 cl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used for stabilization of homeostasis and arresting pathological processes in the body. Invention proposes a pharmaceutical composition as powder with particles size from 250 to 400 mcm comprising the following components by the first variant, wt.-%: carbon, 10.01-53.02; oxygen, 30.10-53.10; potassium, 0.26-1.99, and calcium, 0.20-31.37, and comprising the following components by the second variant, wt.-%: calcium, 0.35-31.20; carbon, 10.99-50.21; oxygen, 34.55-51.03; sulfur, 0.73-14.81, and phosphorus, 0.08-3.30. Invention provides compensation of trace elements unbalance that causes and accompanies many diseases, possibility for stabilization of trace element homeostasis and arresting pathological processes of different etiology.

EFFECT: improved and valuable medicinal properties of composition.

12 cl, 13 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition made mainly as solid medicinal formulations and comprising therapeutically effective amount of gliclazide and the special additive in the amount 4.65-6.70 mass. p. per mass unit of active substance. The additive comprises hydroxypropylmethylcellulose, microcrystalline cellulose, aerosil and stearate taken in the following ratio of components, mass. p. per 1 m. p. of active substance: hydroxypropylmethylcellulose, 2.50-3.50; microcrystalline cellulose, 2.12-3.00; aerosil, 0.01-0.05, and stearate, 0.02-0.15. Proposed pharmaceutical composition provides the sustained-release of gliclazide and high bioavailability of active substance, a simple method for its preparing as compared with solid medicinal formulation of gliclazide known from the prior art.

EFFECT: improved and valuable properties of composition.

3 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.

EFFECT: improved and valuable medicinal properties of preparations.

19 cl, 1 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: method involves administration of amlodipine in the dose 5 mg, once in the same time and metformin in the dose 500 mg, 2 times per 24 h in patients at the background of individually selected hypocaloric diet. Treatment is carried out for 8 weeks, not less. Method provides optimization of intravascular activity of platelets due to correction of primary homeostasis and the level of their antioxidant protection. Invention can be used for rapid optimization of functions of platelets at metabolic syndrome.

EFFECT: improved and enhanced method for optimization.

2 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acylphenylurea of the formula (I) and to their physiologically acceptable salts possessing property of glycogen phosphorylase inhibitors. In compound of the formula (I) A means phenyl and phenyl residue can be substituted three times with fluorine (F), chlorine (Cl), bromine (Br) atoms, -CF3, -NO2, -O-(C1-C6)-alkyl, -SO2-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R1 means hydrogen atom (H), (C1-C6)-alkyl; R2 means H, (C1-C6(-alkyl, -CO-(C1-C6)-alkyl; 3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -O(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, -COOH, -COO-(C1-C6)-alkyl; X means oxygen (O), sulfur (S) atom; R7 means (C1-C10)-alkylene-COOH, (C1-C10)-alkylene-COO-(C1-C6)-alkyl, (C1-C10)-alkylene-NH2, (C1-C10)-alkylene-NH-(C1-C6)-alkyl, (C1-C10)-alkylene-N-[(C1-C6)-alkyl]2, (C1-C10)-alkylene-B wherein B means piperidinyl or furyl. Also, invention relates to a pharmaceutical composition and a method for preparing the pharmaceutical composition. Proposed compounds can be used for preparing pharmaceutical composition useful for declining level of blood glucose and for treatment of diabetes mellitus type II.

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

7 cl, 2 sch, 2 tbl, 1 ex

FIELD: medicine, endocrinology.

SUBSTANCE: treatment involves prescription to patient light water as drinking water with the total mineralization 200-500 mg/l, the deuterium content 100 ppm, not above, and the oxygen-18 content 1800 ppm, not above, on the background of dietetic therapy and insulin therapy or intake of hypoglycemic preparations in the daily dose 1000-1500 ml. The first intake is carried out before eating in the morning in the dose 200-250 ml and the remaining amount for a day, 30-40 min before eating or in breaks of eating every day. The curative course is from 28 to 45 days. Method provides declining the blood glucose content and to improve metabolic processes.

EFFECT: improved treatment method.

2 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to O-arylglucoside inhibitors of SGLT2 of the formula (I): wherein Y means compounds of formulae: A means -O(CH2)m, sulfur atom (S), -NH(CH2)m or -(CH2)n wherein n = 0-3; m = 0-2; R1-R6 are determined above, and to a pharmaceutical composition based on thereof, and to methods for treatment of diabetes mellitus type 2, and micro- and macrovascular diabetic complications.

EFFECT: valuable medicinal properties of inhibitors.

15 cl, 1 tbl, 99 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid
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