Derivatives of tetrahydropyridine and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

 

The invention relates tetrahydropyridine derivatives or their pharmaceutically acceptable salts, which possess antiproliferative activity, such as antitumor activity, and therefore can be used in the methods of treatment of humans or animals. In addition, the invention relates to a method of obtaining the above tetrahydropyridine derivatives, to pharmaceutical compositions containing these compounds and to their use in the manufacture of medicinal products intended for the stimulation of antiproliferative action in warm-blooded animal such as man.

The level of technology

Regulation of transcription is a key event in cell differentiation, proliferation and apoptosis. Transcriptional activation of several genes determines the fate of cells, and therefore the transcription is tightly regulated by many factors. One of its regulatory mechanisms includes a way to change the tertiary structure of DNA, which affects transcription through changes in the availability of those segments of DNA that are targets of transcription factors. The degree of integration of the nucleosome is governed by the degree of acetylation of histones bark. At lower levels of acetylation nuclesome Packed tight enough and, therefore, the process of transcripti is impossible. On the other hand, when the acetylation of histones bark of the nucleosome relaxes, allowing you to develop the process of transcription. The degree of acetylation of histones depends on the balance of activity distancedistance (GAT) and discontiuation (HDAC). Recently found that HDAC inhibitors stop the growth of and induce apoptosis in some types of tumor cells, including cells of the colon, T-cell lymphoma and erythroleukemia cells. If we assume that the decisive factor (stop) of tumor progression is apoptosis, HDAC inhibitors are promising agents for the treatment of tumors as effective inducers of apoptosis (Koyama Y., and others, Blood, 96, 1490-1495 (2000)).

Identified several structural classes of HDAC inhibitors, which are considered in the review Marks P.M., J. Natl. Cancer. Inst. 92, 1210-1216 (2000). More specifically, in WO 98/55449 and US 5369108 described alkanoyloxy possessing inhibitory activity against HDAC.

Recently found that some tetrahydropyridine derivatives possess anti-proliferative properties that are superior to the activity of the compounds described in the cited literature. These properties due to the presence of inhibitory activity against HDAC.

Description of the invention

The present invention features the production is the same tetrahydropyridine of the formula I

where

(a) means a phenyl group which is unsubstituted or substituted 1, 2 or 3 substituents, independently selected from the series halogen, C1-C4alkyl-, trifluoromethyl-, hydroxy-, With1-C4alkoxy, benzyloxy, C1-C3alkylenedioxy-, nitro-, amino-, With1-C4alkylamino-, di(C1-C4alkyl)amino, C1-C4alkanolamine-, or phenyl group which is unsubstituted or substituted 1, 2 or 3 substituents, independently selected from the series chlorine, With1-C4alkyl-, trifluoromethyl-, hydroxy-, With1-C4alkoxy, C1-C3alkylenedioxy-, nitro-, amino-, C1-C4alkylamino-, di(C1-C4alkyl)amino - and C1-C4alkanolamine, or

(b) an indolyl group, which is unsubstituted or substituted 1, 2 or 3 substituents, independently selected from the series halogen, C1-C4alkyl-, trifluoromethyl-, hydroxy-, With1-C4alkoxy, benzyloxy, C1-C4alkylenedioxy-, nitro-, amino-, With1-C4alkylamino-, di(C1-C4alkyl)amino or1-C4alkanolamines,

R1and R2are identical or different and mean hydrogen, C1-C4alkyl-, trifluoromethyl - or airgroup,

X Osnach is no alkylenes group with a straight chain, containing 5, 6 or 7 carbon atoms, where one CH2the group could be replaced by oxygen atom or sulfur, or where 2 carbon atoms form a C=C double bond, which is unsubstituted or substituted by one or two substituents selected from a range With1-C4alkyl and halogen,

its enantiomers, diastereoisomers, racemates and mixtures thereof, and pharmaceutically acceptable salts.

Acceptable values Deputy halogen is, for example, fluorine, chlorine, bromine and iodine; acceptable alternates With1-C4alkyl are for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl; acceptable alternates With1-C4alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy; acceptable alternates With1-C4alkylamino are, for example, methylamino, ethylamino or propylamino; acceptable substituents di(C1-C4alkyl)amino include dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino or dipropylamino; acceptable alternates With1-C4alkanolamine are, for example, formylamino, acetamido, propionamido or butyramide; acceptable substituents C1-C3alkylenedioxy are, for example, methylenedioxy, Ethylenedioxy or Propylenediamine.

Suitable pharmaceutically who priemlemoj salt tetrahydropyridine-derivative according to the invention is, for example, an acid additive salt, for example, inorganic or organic acids, for example hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric or maleic acid.

Kannelirovannye cyclic system with the inclusion tetrahydropyridine preferably include 3,4-dihydro-1H-isoquinoline or 1,2,4,5-tetrahydropyrido[4,3-b]indole or 1,3,4,5-tetrahydro-β-carbolin.

Preferred compounds according to the invention are tetrahydropyridine derivatives of the formula I

where

means phenyl, which is unsubstituted or substituted by 1 or 2 substituents independently chosen from a number of hydroxy, C1-C4alkoxy, benzyloxy or phenyl, or

means indolyl, which is unsubstituted or substituted with halogen.

R1and R2are identical or different and mean hydrogen, C1-C4alkyl-, trifluoromethyl - or panelgroup,

X means alkylenes group with a straight chain, containing 5, 6 or 7 carbon atoms, where one CH2the group could be replaced by oxygen atom or sulfur, or where 2 carbon atoms form a C=C double bond, which is unsubstituted or substituted by one or two substituents, selected and from a number of methyl, fluorine and chlorine

their enantiomers, diastereoisomers, racemates and mixtures thereof, and pharmaceutically acceptable salts.

Obtaining the compounds according to the invention

The tetrahydropyridine derivatives of the formula I or their pharmaceutically acceptable salts can be obtained by any method, which is used for obtaining the loved ones in structural connections. Such methods if they are used to obtain the tetrahydropyridine derivatives of the formula I or their pharmaceutically acceptable salts, are also the object of the present invention and are illustrated by the following typical examples in which, unless otherwise stated, A, R1, R2and X have any of the values specified above. The necessary starting materials can be obtained by conventional methods of organic chemistry. The receipt of such starting materials is described, without limitation, in the accompanying examples. Alternatively necessary starting materials may be obtained by methods similar to those described in the proposal, which are known to the expert in the field of organic chemistry.

(a) First, the preferred method of preparing compounds of the formula I is the removal of the protective group in the compounds of formula II

where Y represents an appropriate protective group. The compounds of formula II are new and and included in the scope of the present invention.

Suitable protective groups are benzyl, para-methoxybenzyl-, tert-butyloxycarbonyl, trityl or cellgroup, such as trimethylsilyl or dimethyl-tert-Boticelli-. The reaction is carried out in conditions that depend on the type of the protective group. If the protective group means benzyl or para-methoxybenzyl-, the reaction is carried out by hydrogenolysis in an inert solvent, such as alcohol, methanol or ethanol, in the presence of a catalyst based on a noble metal, such as palladium, on an appropriate medium such as carbon, barium sulfate or barium carbonate, at room temperature and atmospheric pressure. If the protective group means tert-butyloxycarbonyl, trityl or silyl-such as trimethylsilyl or dimethyl-tert-Boticelli-, the reaction is carried out in the presence of acids at temperatures from -20°C to 60°C, preferably from 0°C to room temperature. The acid may be hydrochloric acid in an inert solvent, such as diethyl ether or dioxane, or triperoxonane acid in dichloromethane. If the protective group means cellgroup, such as trimethylsilyl or dimethyl-tert-Boticelli-, the reaction is preferably carried out in the presence of fluoride such as sodium fluoride or tetrabutylammonium fluoride, in an inert solvent such as dichloromethane.

The tetrahydropyridine-derived formula I can be obtained in this way is in free base form or in another embodiment can be obtained in salt form. If salt is necessary to obtain the free base, salt is treated with an appropriate base such as a carbonate or hydroxide of an alkaline or alkaline-earth metal, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.

The compounds of formula II can be obtained by the interaction of the tetrahydropyridine of formula III

where A, R1and R2have the meanings stated above, with a compound of formula IV

where Z denotes a leaving group, and X and Y have the meanings mentioned above, in the absence or in the presence of an appropriate base.

Suitable leaving group Z is, for example, halogen or sulfonyloxy, for example chlorine, bromine, methansulfonate - or para-toluensulfonate-. Suitable base is, for example, an organic amine, for example pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, a carbonate or hydroxide of an alkaline or alkaline-earth metal, for example sodium carbonate, potassium carbonate, sodium carbonate, calc what I sodium hydroxide or potassium hydroxide.

Usually the reaction is carried out in an appropriate inert solvent or diluent, for example in alcohol or ether complex, such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, in a simple ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-ethylpyrrolidin-2-one or dimethylsulfoxide. Usually the reaction is carried out at a temperature of from 10°, 250°C, preferably from 40°to 200°C.

(b) Another preferred method of preparing compounds of the formula I is the interaction of the compounds of formula V

where A, R1, R2and X have the meanings stated above, with hydroxylamine. Typically this reaction is carried out in two stages in one flask. In the first stage, activate the carboxylate of the formula V. This reaction is carried out in an inert solvent or diluent, for example, dichloromethane, dioxane or tetrahydrofuran, in the presence of an activating agent. Suitable reactive derivative of the acid is, for example, allalone, such as acylchlorides, obtained by the reaction of acid with chlorine is Gericom inorganic acid, for example thionyl chloride; a mixed anhydride, for example an anhydride, obtained by the interaction of the acid with CHLOROFORMATES, such as isobutylparaben; an activated ester, for example, obtained by interaction of the acid with a phenol such as pentafluorophenol; complex ester, such as pentaftorosilikata, or with alcohol, such as methanol, ethanol, isopropanol, butanol or N-hydroxybenzotriazole; acylated, such as azide, obtained by interaction of the acid with an azide, such as diphenylphosphoryl; achilleid, such as cyanide, obtained by interaction of the acid with a cyanide such as diethylphosphoramidite; or the reaction product of the acid with a carbodiimide such as dicyclohexylcarbodiimide. The reaction is carried out at a temperature of from -30°C to 60°usually at 0°With or below. In the second stage to the solution was added hydroxylamine at a temperature of activation and the temperature is slowly increased to room temperature.

The compounds of formula V is obtained by hydrolysis of compounds of formula VI

where A, R1, R2and X have the meanings indicated above, a R means an alkyl group such as methyl, ethyl or tert-butyl or benzyl. Reaction conditions of the hydrolysis depends on the nature of the group R3. If R3means methyl or ethyl, the reaction is carried out in the presence of bases of the tion, such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an inert solvent or diluent, for example methanol or ethanol. If R3means tert-butyl, the reaction is carried out in the presence of acid, for example hydrochloric acid in an inert solvent, such as diethyl ether or dioxane, or triperoxonane acid in dichlormethane. If R3means benzyl, the reaction is carried out by hydrogenolysis in the presence of a catalyst based on a noble metal, such as palladium, on an appropriate medium such as coal.

The compounds of formula VI are obtained from compounds of formula III

where A, R1and R2have the values specified above, the reaction with compounds of formula VII

where Z, X and R3have the meanings specified above, in the absence or in the presence of an appropriate base.

Suitable base is, for example, an organic amine, such as pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, a carbonate or hydroxide of an alkaline or alkaline-earth metal, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.

Usually the reaction Provo the Yat in the presence of a suitable inert solvent or rabbanites, for example, alcohol or a complex ether, such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, in a simple ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-ethylpyrrolidin-2-one or dimethylsulfoxide. Usually the reaction is carried out at a temperature of from 10°, 250°C, preferably from 40°to 200°C.

The compounds of formula III can be obtained by the known methods, for example, described O. Hoshino, etc. The Chemistry of Heterocyclic Compounds, E.C.Taylor, ed. V. 38, part 3, from C, Wiley, New York (1995), or Mor E.D. and Cook J.M., Chem. Rev., 95, 1797-1842 (1995), or D. Badia and other Trends Heterocycl. Chem., 2, 1-11 (1991).

(C) a Third preferred method of preparing compounds of the formula I is the interaction of the compounds of formula VIII

where A, R1, R2and X have the meanings indicated above, a R4means1-C4alkyl, for example methyl or ethyl, with hydroxylamine in the presence of an appropriate base.

The reaction is carried out in an inert solvent or diluent, such as methanol or ethanol, at temperatures from 0°to 100°usually at room or approximately at room tempera is ur, and at pH 9 to 11.

Suitable base is, for example, the alcoholate such as sodium methylate.

(g) Compounds of the formula I in which one of the substituents means an amino group, get the restoration derivative compounds of formula I, where the Deputy means the nitrogroup. The restoration carried out by any of many known methods used for this modification. For example, recovery can be carried out by hydrogenation of a solution of nitro compounds in an inert solvent or diluent as above, in the presence of an appropriate catalyst based on a metal such as palladium or platinum. Other regenerating agent is, for example, activated metal, such as activated iron (obtained by treatment of iron powder diluted acid, such as hydrochloric acid). Thus, recovery can be performed, for example, by heating a mixture of nitro compounds, and the activated metal in an appropriate solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, at a temperature of, for example, from 50°to 150°usually at room or approximately at room temperature.

d) the compounds of formula I, where one of the substituents means C1-C4alkanolamines, ucaut by acylation derivative of the formula I, where one of the substituents means the amino group. Suitable allermuir agent is, for example, any agent known in the art, which allerpet the amino groups with the formation of alluminare, such as allalone, such as alcoholclone or alkanolamide, usually in the presence of an appropriate base, as specified above, the anhydride alanovoy acid or a mixed anhydride, for example acetic anhydride, or mixed anhydride obtained by the reaction of alanovoy acid with alkoxycarbonylmethyl, such as alkoxycarbonylmethyl, in the presence of an appropriate base, above. In General, the acylation is carried out in an appropriate inert solvent or diluent as above, at a temperature of, for example, from -30°to 120°usually at room or around room temperature.

As another object, the invention features a pharmaceutical composition that includes tetrahydropyridine-derived formula I or its pharmaceutically acceptable salt, above, in a mixture with a pharmaceutically acceptable diluent or carrier. The composition can be manufactured in the form for oral administration, for example in the form of a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, is nutricosmetic introduction or injection) in the form of a sterile solution, suspension or emulsion, for topical introduction in the form of an ointment or cream or for rectal administration in the form of a suppository. In General these compositions can be produced in a mixture with conventional excipients. The tetrahydropyridine usually do a warm-blooded animal at a standard dose, which contains from 5 to 5000 mg per square meter body of the animal, i.e. approximately 0.1-100 mg/kg, usually it is therapeutically effective dose. The standard dose is in the form of a tablet or capsule typically contains, for example, about 1-250 mg of the active ingredient. The preferred daily dose is from 1 to 50 mg/kg, However, the daily dose may vary depending on the patient, the route of administration and the severity of the disease. The optimal dose determines the practitioner who treats a particular patient.

As another object the present invention proposes the use of a tetrahydropyridine-derived formula I having the values specified above, in the method of treatment of a human or animal. Now unexpectedly found that compounds of the present invention possess anti-proliferative properties due to the presence of inhibitory activity against discontiuation. Therefore, the compounds of the present invention can be used in the method of suppressing prolifer the tion of malignant cells. Therefore, it is expected that the compounds of the present invention can be used in the treatment of neoplastic diseases due to the presence of antiproliferative actions, primarily in the treatment of cancer of breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary. In addition, it is assumed that the connection of the present invention may have activity against several leukemia, malignant neoplasms of lymphoid tissues and solid tumors, such as carcinomas and sarcomas in tissues, such as liver, kidney, prostate and pancreas.

Thus, as the specified object in the invention features the use of a tetrahydropyridine-derived formula I or its pharmaceutically acceptable salt having the values specified above, in the manufacture of a medicinal product for use to stimulate antiproliferative actions in the body of warm-blooded animal such as man.

In addition, as the specified object in the invention features a method of promoting antiproliferative actions in the body of warm-blooded animal such as man that is in need of such treatment, and this method includes the introduction of specified animal now what about the number of tetrahydropyridine-derived, above.

The above antiproliferative treatment can be carried out if treatment with a single drug or in conjunction with one or more other anti-tumor substances, for example, selected from the group comprising inhibitors of mitosis, for example vinblastine; alkylating agents, for example CIS-Platin, carboplatin and cyclophosphamide; inhibitors of the Assembly of microtubules, for example paclitaxel or other taxanes; antimetabolites, for example 5-fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or, for example, intercalaries antibiotics, for example adriamycin and bleomycin; immunomodulators, such as trastuzumab; inhibitor of DNA synthesis, such as gemcitabine; enzymes, for example asparaginase; topoisomerase inhibitors, for example etoposide; biological response modulators, for example interferon; antihormones such as antiestrogens, such as tamoxifen or, for example antiandrogens such as 4'-cyano-3-(4-perpenicular)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide, or other therapeutic agents or means, as described, for example, V.T. DeVita, Jr., Hellmann s, Rosenberg SA, Cancer: Principles and Practice of Oncology, 5thed., Lippincott-Raven Publishers (1997). Such combination therapy can be carried out with the simultaneous, sequential or separate introduction of the individual components. This object of the invention offer the W of the pharmaceutical product, including tetrahydropyridine-derived formula I, above, and above additional antitumor substance, for a combined therapy of neoplastic diseases.

The invention is illustrated by the following, without limitation, examples, and unless otherwise noted, these examples:

(I) the evaporation is carried out in vacuum on a rotary evaporator, and the subsequent processing is carried out after separation of solid material, such as dryers, filtration;

(II) the reaction is conducted at room temperature, i.e. from 18°C to 25°and in the atmosphere of inert gas such as argon or nitrogen;

(III) chromatography (Express chromatography and liquid chromatography high resolution (IHVR) carried out on silica gel (Kieselgel Merck) or on silica gel to reverse-phase chromatography (Lichroprep RP-18) (company Emagic, Darmstadt, Germany);

(IV) outputs are provided for illustration only and do not necessarily indicate the maximum possible output;

(V) the melting point was determined on the device for the automatic determination of the melting temperature Mettler SP62, when heated on an oil bath or on the table of Kofler;

(VI) the structure of the final products of the formula I were confirmed by nuclear methods (generally proton) magnetic resonance (NMR) and mass spectrometry (mass spectrometer Micromass Platform II is using APCI or mass spectrometer Micromass Platform ZMD using electrospray);

(VII) intermediate compounds usually characterized only by a few parameters, and the purification was performed by thin-layer chromatography (TLC).

Example 1

Hydroxyamide 8-(3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid

(a) To a suspension of 3.2 g (20 mmol) of the hydrochloride of O-benzylhydroxylamine in 150 ml of dichloromethane in an ice bath was added 14 ml of triethylamine and stirred until a clear solution is formed. Then added 4.5 g (20 mmol) of omega-bromooctanoate acid and 5.6 g (22 mmole) of bis(2-oxo-3-oxazolidinyl)phosphorylchloride and stirred at room temperature for 18 hours the Solution twice with portions of 150 ml was extracted with 1 M hydrochloric acid and twice with portions of 150 ml of 1 M aqueous solution of sodium bicarbonate. The organic solvent is evaporated in vacuum, thus received of 5.1 g (78%) of benzylcyanide 8-bromooctanoate acid in the form of a colorless oil. MS: 330 (M+N+).

(b) a Solution of 0.39 ml (3,12 mmole) of 1,2,3,4-tetrahydroisoquinoline, 1.08 g (3.3 mmole) of benzylcyanide 8-bromooctanoate acid and 0.46 g (3.3 mmole) of potassium carbonate in 12 ml of acetonitrile was heated under reflux for 2 hours After cooling to room temperature, added water and was extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated solution is tel. The residue was purified by reversed-phase GHUR when elution with methanol, was obtained 1 g (84%) of benzylcyanide 8-(3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid as a colourless oil. MS: 381 (M+N+).

(in) 200 mg (of 0.53 mmole) of benzylcyanide 8-(3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid in 30 ml of methanol was hydrogenosomal in the presence of palladium on barium sulphate at room temperature and atmospheric pressure for 1 h, the Catalyst was separated by filtration and the solvent evaporated. It was obtained 150 mg (98%) of hydroxyamide 8-(3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid as an amorphous solid. MS: 291 (M+N+).

Example 2

Hydroxyamide 8-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid

(a) Benzylamine 8-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid was obtained in the form of almost colorless wax (0.28 g, yield 49%), MS: 441 (M+N+), the interaction of 0.3 g (1.3 mmole) of benzylcyanide 8-bromooctanoate acid (obtained as described in example 1(a)) from 0.43 g (1.3 mmole) of the hydrochloride of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in DMF in the presence of potassium carbonate (0.18 g, 1.4 mmole) in the same way as described in example 1 (b). The product was purified by chromatography on a column of silica gel (eluent: ethyl acetate/methanol, 9:1).

(b) Specified in the header with inania was obtained as amorphous solid (yield 98%), MS: 351 (M+N+), hydrogenomonas of benzylcyanide 8-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid in the same way as described in example 1(b).

Example 3

Hydroxyamide 8-(1-isopropyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid

(a) Benzylamine 8-(1-isopropyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid was obtained in the form of almost colorless wax (0.1 g, yield 20%), MS: 483 (M+N+), the interaction of 0.3 g (1.1 mmole) of benzylcyanide 8-bromooctanoate acid (obtained as described in example 1(a)) with 0.3 g (1.1 mmole) of the hydrochloride of 1-isopropyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in DMF in the presence of potassium carbonate (0.15 g, 1.1 mmole) in the same way as described in example 1 (b). The product was purified by chromatography on a column of silica gel (eluent: ethyl acetate).

(b) Specified in the title compound was obtained as amorphous solid, MS: 393 (M+N+), hydrogenomonas of benzylcyanide 8-(1-isopropyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid in the same way as described in example 1(b).

Example 4

Hydroxyamide 8-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid

(a) Benzylamine 8-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid, the floor is made in the form of almost colorless wax (0.35 g, yield 37%), MS: 455 (M+N+), the interaction of 0.7 g (2.1 mmole) of benzylcyanide 8-bromooctanoate acid (obtained as described in example 1(a)) with 0.5 g (2.1 mmole) of the hydrochloride of 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline in DMF in the presence of potassium carbonate (0.3 g, 2.2 mmole) in the same way as described in example 1 (b). The product was purified by chromatography on a column of silica gel (eluent: ethyl acetate/methanol, 95:5).

(b) Specified in the header sochinenie received in the form of almost colorless oil (yield 98%), MS: 365 (M+N+), hydrogenomonas of benzylcyanide 8-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid in the same way as described in example 1(b).

Example 5

Hydroxyamide 8-(6,7-diethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid

(a) Benzylamine 8-(6,7-diethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid was obtained in the form of almost colorless wax (0.15 g, yield 27%), MS: 469 (M+N+), the interaction of 0.38 g (1.2 mmole) of benzylcyanide 8-bromooctanoate acid (obtained as described in example 1(a)) with 0.3 g (1.2 mmole) of the hydrochloride 6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline in DMF in the presence of potassium carbonate (0.16 g, 1.2 mmole) in the same way as described in example 1 (b). The product was purified by chromatography on a column of silica gel (eluent: ethyl acetate/methanol, 9:1).

(b) the Decree of the TES in the header cadinene was obtained as amorphous solid (yield 98%), MS: 379 (M+N+), hydrogenomonas of benzylcyanide 8-(6,7-diethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid in the same way as described in example 1(b).

Example 6

Hydroxyamide 8-(6,7-dimethoxy-1-phenyl-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid

(a) Benzylamine 8-(6,7-dimethoxy-1-phenyl-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid as an amorphous solid (0.12 g, yield 23%), MS: 517 (M+N+), the interaction of 0.3 g (1.1 mmole) of benzylcyanide 8-bromooctanoate acid (obtained as described in example 1(a)) with 0.32 g (1 mmol) of the hydrochloride of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline in DMF in the presence of potassium carbonate (0.14 g, 1 mmol) in the same way as described in example 1 (b). The product was purified by chromatography on a column of silica gel (eluent: ethyl acetate/heptane, 1:1).

(b) Specified in the title compound was obtained as amorphous solid (yield 98%), MS: 427 (M+N+), hydrogenomonas of benzylcyanide 8-(6,7-dimethoxy-1-phenyl-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid in the same way as described in example 1(b).

Example 7

Hydroxyamide 8-(1,3,4,9-tetrahydro-(3-carbolin-2-yl)octanoic acid

(a) Benzylamine 8-(1,3,4,9-tetrahydro-β-carbolin-2-yl)octanoic acid was obtained as amorphous solid substances the government (0.18 g, a 30%yield), MS: 420 (M+N+), the interaction of 0.5 g (1.5 mmole) of benzylcyanide 8-bromooctanoate acid (obtained as described in example 1(a)) with 0.25 g (1.4 mmole) of 1,2,3,4-tetrahydro-N-pyrido[3,4-b]indole in DMF in the presence of potassium carbonate (0.2 g, 1.4 mmole) in the same way as described in example 1(b). The product was purified by chromatography on a column of silica gel (eluent: ethyl acetate).

(b) Specified in the header connection was obtained as amorphous solid (yield 98%), MS: 330 (M+N+), hydrogenomonas of benzylcyanide 8-(1,3,4,9-tetrahydro-β-carbolin-2-yl)octanoic acid in the same way as described in example 1(b).

Example 8

The following compounds were obtained in the same way as described in examples 1-7:

(a) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)heptane acid,

(b) hydroxyamide 6-(3,4-dihydro-1H-isoquinoline-2-yl)hexanoic acid,

(C) hydroxyamide 8-(3,4-dihydro-6-phenyl-1H-isoquinoline-2-yl)octanoic acid,

(d) hydroxyamide 8-(3,4-dihydro-7-phenyl-1H-isoquinoline-2-yl)octanoic acid,

(e) hydroxyamide 8-(1-trifluoromethyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)octanoic acid

(e) hydroxyamide 8-(6-fluoro-1,3,4,5-tetrahydropyrido[,3-b]indol-2-yl)octanoic acid,

(g) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-5-methylheptanoic acid,

(C) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-4-methylheptanoic acid,

(and) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-3-methylheptanoic acid,

(K) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-2-methylheptanoic acid,

(l) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-2-chloroheptane acid,

(m) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-2,2-dimethylheptane acid,

(h) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-2,2-dichlorophenol acid

(o) hydroxyamide 8-(3,4-dihydro-1H-isoquinoline-2-yl)-2-methyloctanoic acid,

(p) hydroxyamide 6-(3,4-dihydro-1H-isoquinoline-2-yl)-2-methylhexanoic acid,

(p) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-4-axiatonal acid,

(C) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-3-methyl-4-axiatonal acid,

(t) hydroxyamide 7-(3,4-Digi the ro-1H-isoquinoline-2-yl)-3-axiatonal acid,

(u) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-3-oxa-5-CIS-heptenophos acid,

(f) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-3-oxa-5-TRANS-heptenophos acid,

(x) hydroxyamide 7-(3,4-dihydro-1H-isoquinoline-2-yl)-2-methyl-3-oxa-heptane acid.

Example 9

Determination of the inhibitory properties of the compounds according to the invention in respect of HDAC

To determine the inhibitory properties of the compounds according to the invention in respect of HDAC we developed testing using as a substrate the enzyme aminocoumarin-ω-acetylglycine. More details on this analysis are described K. Hoffman and other Nucleic Acids Research, 27, 2057-2058 (1999). In the described method the inhibitory activity of the new compounds were determined at a concentration of 10 nm. The degree of inhibition determined for individual compounds are given in table 1.

Table 1
The connection specified in the header of the example No.The inhibitory activity (%) at a concentration of 10 nm
154
526
626
726

Farmace the political composition

Below is preferred pharmaceutical composition

(a) Composition for tablets (Wet granulation)

Then. roomIngredientsmg/tab.
1.The compound of the formula I525100500
2.Betwedn. lactose DTG12510530150
3.Krahm.-Rx 150066630
4.Microcrystalline303030150
5.Magnesium stearate1111
Total167167167831

Method of delivery:

Mix the ingredients 1, 1, 3, and 4 and granularit with purified water, dry the granules at 50°pass the granules through a suitable grinding device, and then add the component 5 and stirred for three minutes. Then tabletirujut in the usual way using pressing.

b) Encapsulation
Then. roomIngredientsmg/caps.
1.The compound of the formula I525100500
2.Water lactose159123148-
3.Corn starch25354070
4.Talc10151025
5.Magnesium stearate1225
Total200200300600

Method of delivery:

Mix the ingredients 1, 2 and 3 in a suitable mixer for 30 minutes, then add the components 4 and 5 and mix for another 3 minutes. The mixture is filled capsules.

Literature

Badia D. and other Trends Heterocycl. Chem., 2, 1-11 (1991).

Sokh E.D. and Cook J.M., Chem. Rev., 95, 1797-1842 (1995).

DeVita V.T., Jr., Hellmann s, Rosenberg SA, Cancer: Principles and Practice of Oncology, 5thed., Lippincott-Raven Publishers (1997).

Hoffman, K., and other Nucleic Acids Research, 27, 2057-2058 (1999).

Hoshino, O., etc. The Chemistry of Heterocyclic Compounds, E.C.Taylor, ed. V. 38, part 3, s and beyond, Wiley, New York (1995).

Koyama Y., etc. Blood, 96, 1490-1495 (2000).

Marks P.M., J. Natl. Cancer. Inst. 92, 1210-1216 (200).

US 5369108.

WO 98/55449.

1. Derivatives tetrahydropyridine formula I

where

(a) means a phenyl group which is unsubstituted or substituted 1, 2 or 3 substituents, independently selected from C1-C4alkoxy, or

(b) means indolenine group, which is unsubstituted, R1and R2are the same or differentiating and mean hydrogen, C1-C4alkyl or phenyl group,

X means alkylenes group with a straight chain, containing 5, 6 or 7 carbon atoms, and pharmaceutically acceptable salts.

2. The compound of formula I according to claim 1, where

means a phenyl group which is unsubstituted or substituted by 1 or 2 substituents, independently selected from C1-C4alkoxygroup, or

means unsubstituted indolenine group,

R1and R2are the same or different and mean hydrogen, C1-C4alkyl or

phenyl group,

X means alkylenes group with a straight chain, containing 5, 6 or 7 carbon atoms, and pharmaceutically acceptable salts.

3. The compound of formula I in P1 or 2, selected from the group including

hydroxyamide 8-(3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid,

hydroxyamide 8-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid,

hydroxyamide 8-(1-isopropyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid,

hydroxyamide 8-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid,

hydroxyamide 8-(6,7-diethoxy-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid,

hydroxyamide 8-(6,7-dimethoxy-1-phenyl-3,4-dihydro-1H-isoquinoline-2-yl)octanoic acid,

hydroxyamide 8-(1,3,4,9-tetrahydro-β-carbolin-2-yl)octanoic acid.

4. Pharmaceutical composition having inhibitory activity against HDAC containing as active ingredient a compound of the formula I according to claims 1 to 3, in a mixture with a pharmaceutically priemlemim excipient or diluent.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

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

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes new 7-azaindoles of the general formula (I): wherein n = 1 or 2; R1 means mono- or multi-unsaturated, linear or branched (C2-C10)-alkenyl, linear or branched, unsubstituted (C1-C10)-alkyl that can be monosubstituted with (C1-C6)-alkoxy-group, naphthyl, pyridinyl, (C3-C6)-cycloalkyl, phenyl that, in turn, can be substituted with (C1-C6)-alkyl, halogen atom, (C1-C6)-alkoxy-group or hydroxy-group, or radical of the formula: ; R2 and R3 are similar or different being only one of them can mean hydrogen atom and mean (C1-C5)-alkyl possibly substituted with -O-(C1-C6)-alkyl or pyridyl, phenyl possibly substituted twice with -F, -Cl, -Br, -O-(C1-C3)-alkyl or monosubstituted with -COOH or -COO-(C1-C3)-alkyl, pyridyl possibly twice substituted with -Cl, -Br, or group of formulae: or , or R2 and R3 in common with N-atom mean: or under condition that if n = 1 then they don't mean simultaneously: R1 - (C1-C6)-alkyl; R2 - hydrogen atom (H) or (C1-C6)-alkyl, and R3 or wherein R and R' mean independently -Cl or -Br. These compounds possess inhibitory activity with respect to activity of phosphodiesterase 4. Also, invention relates to a medicinal agent comprising these compounds, methods for its preparing and using these compounds for preparing medicinal agents.

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

17 cl, 6 tbl, 40 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

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

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

The invention relates to a derivative tetrahydroisoquinoline formula (I), where X1and X2are hydrogen, halogen, alkoxy - or nitro-group; Y is oxygen or sulfur; R1is hydrogen, alkyl, phenylalkyl or CONHR' wherein R' is phenyl; R2and R3are the same or different from each other and are independently selected from the group consisting of hydrogen and alkyl; R4is hydrogen or lower alkyl

The invention relates to a method for producing 1-substituted 3,3-dimethyl-3,4-dihydroisoquinolines formula (I), where R=OMe; Me; X=Me; SMe; Ph; CH2COOEt; CH2CONH2who is that in an environment of concentrated sulfuric acid at the same time introducing somelady aldehyde, 1,2 - or 1,4-dimethoxy- (or dimethyl) substituted benzene, NITRILES of the formula RCN where R=Me; SMe; Ph; CH2COOEt; CH2CONH2) at a molar ratio of reagents, respectively, 1:1:1

The invention relates to new bellrowan derivatives of dihydropyridines possess biological activity, and more particularly to derivatives of isoquinoline and their salts of the formula I

< / BR>
in which R1and R2independent from each other and denote hydroxyl, alkoxy with 1 to 4 carbon atoms, halogen, alkyl with 1-4 carbon atoms, benzyloxy; In - group-O-, -S - or-СНR5in which R5means hydrogen or alkyl with 1 to 6 carbon atoms; R3- 2 - or 3-thienyl, cycloalkyl with 4-7 carbon atoms, or a group of the formula

< / BR>
where R6means halogen or alkoxy with 1 to 4 carbon atoms, u is 0, 1 or 2; R4alkenyl with 3-6 carbon atoms, unsubstituted or substituted phenyl, alkyl with 1 to 13 carbon atoms, possibly substituted by a Deputy from the group including thienyl, substituted, cyclohexyl, benzyloxy group, phenoxy group and phenyl, the latter or contained in phenoxy-phenyl group can be mono-, di - or triamese residue from the group comprising hydroxyl, alkoxy with 1 to 4 carbon atoms, halogen, trifluoromethyl, nitrogen dioxide and alkyl with 1 to 4 carbon atoms, or TLD is< / BR>
where R7means halogen and trifluoromethyl, nitrogen dioxide, and v is 0, 1,2, or their salts with physiologically tolerated acids or complexing agents

The invention relates to new unsaturated derivatives of hydroximino acid formula

< / BR>
where R1means phenyl, optionally substituted by 1-3 substituents selected from the group comprising FROM1-2alkoxygroup, halogen, or represents a 6-membered unsaturated heterocyclic group containing one nitrogen atom as a heteroatom, and R2means hydrogen or R1together with R2form5-7-cycloalkyl group, Y represents hydrogen, a hydroxy-group,3-22-alkanoyloxy, X means halogen, a hydroxy-group or amino group, R3represents a group of formula-NR4R5where R4and R5mean independently from each other hydrogen, C1-5is an alkyl group, or R4and R5form with the adjacent nitrogen atom a 5 - or 6-membered saturated heterocyclic group which may contain an oxygen atom and may be condensed with a benzene ring, in addition, its geometrical and/or optical isomers and/or pharmaceutically acceptable acid salt additive

The invention relates to new derivatives of Anthranilic acid of the formula I, where R, R1, R2are H, alkyl, HE, alkoxy, halogen, nitro, N(R10R11), R3is H, alkyl, R4is alkyl or R4denotes-CH2- or-CH2CH2- attached or in position 2 cycle b, completing a saturated 5 - or 6-membered nitrogen cycle, or in position 2 of the cycle and is associated with X, which is a simple link, completing a saturated 5 - or 6-membered nitrogen-containing loop, R5is H, HE, alkyl, X represents a simple bond, O, S, -O-(CH2)p-, where p is a number from 1 to 6, R6is H, alkyl, alkoxy, q is a number from 0 to 1, AG denotes phenyl, naphthyl or heterocyclic group containing S or N, each of R7and R8is H, alkyl, alkoxy, hydroxy, phenyl, -NHOH, nitro, N(R10R11), SR12or each of R7and R8forms together with the carbon atoms of the benzene or methylendioxy Deputy, R9denotes phenyl or heterocyclic group containing 1 or 2 O, S, or N, n is the number 0 or 1, m is the number 0 or 1 to 3

The invention relates to compounds of formula I:

< / BR>
where X represents CH2, CO, CS or SO2,

Y is selected from:

direct connection (i.e

The invention relates to bicyclic compounds having a core formed of two condensed six-membered cycles, such as isoquinoline, izoliranim, tetrahydronaphthalene, dihydronaphthalene or tetralone, replaced both acidic and basic functional groups, which are useful in the inhibition of aggregation of erythrocytes
Up!