Derivatives of 1,2,3,4-tetrahydrothieno[3,2-c]pyridine, methods for their preparation and compositions on their basis

 

(57) Abstract:

The invention relates to the field of organic chemistry. Describes derivatives of 1,2,3,4-tetrahydrothieno[3,2-C]pyridine of General formula

< / BR>
its N-oxide form, pharmaceutically acceptable salt or accession or stereochemical isomeric form, where each R1independently represents hydrogen, halogen, C1-6alkyl, nitro-group or1-4alkyloxy; Alk represents C1-6alcander; n = 1 or 2; D represents 1 - or 2-benzimidazolyl, 2(3H)benzoxazolone-3-yl or a radical of the formula

< / BR>
< / BR>
< / BR>
< / BR>
each X is S; R2represents C1-6alkyl, aryl or arils1-6alkyl; R3is1-6alkylthio; R4, R5, R6, R7, R8, R10and R11each, independently, represents hydrogen or C1-6alkyl; R9represents aryl or R3and R4together may form a bivalent radical -3- R4formula (a-2) or (a-5): -CH2-CH2-CH2-CH2- (a-2); -CH=CH-CH=CH- (a-5), where one or two hydrogen atoms of these radicals are each, independently, may be replaced by halogen, C1-6the alkyl, aryls1-6the alkyl, trial to be replaced arils1-6alkylidene; or R3-R4- can also have the formula (a-6), (7), (8), (a-11) or (a-14): -S-CH2-CH2- (and-6); -S-CH2-CH2-CH2- (a-7); -S-CH=CH- (a-8); -NH-CH-CH- (a-11); -CH=CH-O- (a-14) where from one to three hydrogen atoms of these radicals, each independently, may be replaced by C1-6the alkyl and aryl represents phenyl or phenyl substituted WITH1-6the alkyl. Also describes how to obtain the compounds of formula (1), the composition having antagonistic activity against Central-adrenergic receptors, and the composition is suitable for treatment of diseases associated with a deficiency of norepinephrine in the Central or peripheral nervous system. The technical result obtained new compounds with useful biological properties. 6 C. and 6 C.p. f-crystals, 6 PL.

The invention relates to derivatives of 1,2,3,4-tetrahydrothieno[3,2-C] pyridine, which has antagonistic activity against Central2-adrenergic receptors. It also applies to receive them, compositions containing them and their use as pharmaceuticals.

It is known that the Central antagonists 2-adrenergic receptors increase wysw yuushi control over the release of this neurotransmitter. Due to increasing concentrations of noradrenaline,2antagonists can be used in the clinic for treatment or prevention of depression, cognitive disorders, Parkinson's disease, diabetes, sexual dysfunction and impotence, increased intraocular pressure, and diseases associated with disorders of intestinal peristalsis, because all these States are associated with deficiency of norepinephrine in the Central or peripheral nervous system.

Compounds of the present invention are new and have specific and selective affinity to various well-known subtypes2-adrenergic receptors, i.e., K2A-,2Band2C-adrenergic receptors.

The present invention relates to compounds of the formula

< / BR>
their N-oxide forms, pharmaceutically acceptable salts connection and stereochemical isomeric forms, where:

each R1independently represents hydrogen, halogen, C1-6alkyl, nitro, hydroxy or C1-4alkyloxy;

Alk represents C1-6alcander;

n is 1 or 2;

D represents 1 - or 2-benzimidazolyl, 2(3H)benzoxazolone-3-yl or a radical of the formula

< / BR>
< / BR>
< / BR>
< / BR>
where each X independently BR>R3represents hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino or mono - or di(C1-6alkyl)amino;

R4, R5, R6, R7, R8, R10, R11and R12each independently represents hydrogen or C1-6alkyl;

R9represents hydrogen, C1-6alkyl or aryl; or R3and R4taken together may form a bivalent radical R3-R4formula

- CH2-CH2-CH2- (a-1);

- CH2-CH2-CH2-CH2- (a-2);

- CH=CH-CH2- (and-3);

- CH2-CH=CH- (a-4) or

- CH=CH-CH=CH (a-5);

where one or two hydrogen atoms of these radicals (a-1) to (a-5) each independently may be replaced by halogen, C1-6the alkyl, aryl WITH1-6the alkyl, trifluoromethyl, amino, hydroxy, C1-6alkyloxy or C1-10alkylcarboxylic; or where possible, two genialnyh hydrogen atom may be replaced by C1-6alkylidene or aryl WITH1-6alkylidene; or

-R3-R4- can also be

-S-CH2-CH2- (and-6);

-S-CH2-CH2-CH2- (a-7);

-S-CH=CH- (a-8);

-NH-CH2-CH2- (a-9);

-NH-CH2-CH2-CH1-6the alkyl or aryl; and aryl represents phenyl or phenyl substituted by halogen or C1-6the alkyl.

Used in the previous definitions, the term halogen refers to fluorine, chlorine, bromine and iodine. The term C1-6alkyl defines straight and branched saturated hydrocarbons having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, pentyl, hexyl, etc., the Term C1-10alkyl includes C1-6alkyl radicals and the higher homologues having 7 to 10 carbon atoms, such as, for example, heptyl, octyl, nonyl, decyl, etc., the Term C1-6alcander defines bivalent straight or branched alkadiene radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, 1,6-hexandiol etc.; the term C1-6alkyliden defines bivalent straight or branched alkylidene radicals having from 1 to 6 carbon atoms, such as, for example, methylene, ethylidene, 1-propylidene, 1-butylidene, 1-pentylidene, 1-hexylidene etc.

Salt n is (the compounds of formula (I) can form with suitable acids, such as, for example, inorganic acid, such as halogen acids, for example, chlorodane or bromatologia acid; sulfuric, nitric, phosphoric, etc., acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, amoeba, etc. acids.

Pharmaceutically acceptable salts of accession referred to in this document include therapeutically active non-toxic salt accession grounds, in particular, metals or amines, which are capable of forming compounds of formula (I). These salts can conveniently be obtained by the action of the compounds of formula (I) containing acidic hydrogen atoms, suitable organic and inorganic bases, such as, for example, ammonium salts, salts of alkali and alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium, etc., salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, geranamine salts and salts with aminokislotami appropriate base or acid in free acid or base form.

The term salt of the merger specified in this document also includes a solvate, which the compounds of formula (I) can form, and these solvate is also included in the scope of the present invention. Examples of the solvate include, for example, hydrates, alcoholate, etc.,

The N-oxide forms of the compounds of formula (I) include compounds of formula (I) in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

The term stereochemical isomeric forms, as used herein defines all the possible isomeric forms which the compounds of formula (I) may exist. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms; these mixes contain all diastereoisomers and enantiomers basic molecular structure.

Some of the compounds of formula (I) may also exist in tautomeric forms. Such forms, although it is not stated clearly in the above formula, is also included in the scope of the present invention.

Wherever in this description is not used, the term " compounds of formula (I), it is understood that it also includes the N-oxide forms, farmerettes the compounds of formula (I), in which n is 1, a R1represents hydrogen, halogen, C1-6alkyl or nitro.

An interesting group of compounds are compounds of formula (I) in which n is 1 and R1represents hydrogen, chlorine, fluorine, methyl or nitro, especially where R1represents hydrogen; or in which n is 2 and R1represents methoxy.

Yet another interesting group of compounds are compounds of formula I in which Alk represents methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol or 1.5-pentandiol.

Yet another interesting group of compounds are compounds of formula (I) in which D is 1-benzimidazolyl; 2(3H)benzoxazolone-3-yl or D is a radical of formula (a), in which R3represents C1-6alkylthio, and R4represents C1-6alkyl; or in which R3and R4taken together form a bivalent radical of formula (a-2) or (a-5), where one or two hydrogen atoms of these radicals, each independently, may be replaced by halogen, C1-6the alkyl, aryl WITH1-6the alkyl, trifluoromethyl, amino, hydroxy, C1-6alkyloxy or C1-10alkylcarboxylic; or where possible, two genialnyh hydrogen atom can be semen) or (a-14), where one or where possible two or three hydrogen atoms of these radicals, each independently, may be replaced by C1-6the alkyl or aryl; or D is a radical of formula (b), in which R5and R6submit C1-6alkyl; or D is a radical of formula (C), in which R7represents hydrogen; or D is a radical of formula (d), in which R8represents hydrogen or C1-6alkyl; or D is a radical of the formula (e), in which R9represents aryl; or D is a radical of formula (f), in which X represents S, and R10represents hydrogen; or D is a radical of formula (d), in which X represents S, and R11represents C1-6alkyl.

Specific compounds are compounds of formula (I) in which D is 2(3H)benzoxazolone-3-yl or D is a radical of formula (a), in which R3is methylthio, and R4represents methyl; or in which R3and R4taken together form a bivalent radical of formula (a-2) or (a-5), where one or two hydrogen atoms each independently may be replaced by halogen, C1-6the alkyl, C1-6alkyloxy, aryl WITH1-6the alkyl, trifluoromethyl, amino or SUP> and R4taken together form a bivalent radical of formula (a-6), (7), (8), (a-11) or (14), where one or where possible two or three hydrogen atoms substituted C1-6by alkyl; or D is a radical of formula (b), in which5and R6represent methyl; or D is a radical of formula (C), in which R7represents hydrogen; or D is a radical of formula (d), in which R8represents hydrogen; or D is a radical of the formula (e), in which R9represents aryl attached to the Alk 4 position piperidinol part; or D is a radical of formula (f), in which X represents S, a R10represents hydrogen; or D is a radical of formula (d), in which X represents S, and R11represents methyl.

Preferred are such compounds of formula (I) in which n is 1, R1represents hydrogen, D represents the radical of formula (a), in which R3and R4taken together form a bivalent radical of formula (a-2) or (a-5), where one or two hydrogen atoms each independently may be replaced by halogen, stands, methoxy, arylmethyl, trifluoromethyl, amino or hydroxy; or where two genialnyh hydrogen atom may be replaced by the -7), (a-8), (a-11) or (14), where one or where possible two or three hydrogen atoms are replaced by stands.

Most preferred are the following compounds:

3-[2-[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl] ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one;

6-[[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl] ethyl] -7-methyl-3H-thiazolo[3,2-a]pyrimidine-5-he;

6-[[3,4-dihydrobenzofuran[3,2-e] pyridine-2(1H)-yl] ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine-5-he;

3-[2-[3,4-dihydrobenzofuran[3,2-e] pyridine-2(1H)-yl] ethyl] -2,7-dimethyl-4H-pyrido[1,2-a] pyrimidine-4-one; and their N-oxides, pharmaceutically acceptable salts connection and stereochemical isomeric form.

The compounds of formula (I) can usually be obtained by N-alkylation derivative of 1, 2, 3, 4 tetrahydroxybenzophenone[3,2-C]pyridine of formula (II) alkylating reagent of formula (III) according to the procedure described in EP-A-0 037 265, EP-A-0 053 070, EP-A-0 196 132 and EP-A-0 378 255.

< / BR>
In the intermediate compound (III) W1provides a suitable reaction removable group, such as, for example, halogen, for example chlorine, bromine or iodine; sulfonyloxy, for example, methanesulfonate, 4-methylbenzenesulfonate.

In this and subsequent reactions, the reaction products can the am, such as extraction, crystallization, rubbing and chromatography.

The compounds of formula (I), where D represents the radical of formula (a) represented by the formula (1-a), can be obtained by removing protection from the intermediate N-protected substances of the formula (IV) in which R represents a protective group such as, for example, C1-4allyloxycarbonyl, and subsequent N-acylation of the obtained intermediate product acyl derivative of formula (V), where W2provides a suitable reaction removable group, such as, for example, halogen.

< / BR>
The compounds of formula (I) in which D represents the radical of formula (f), represented by formula (I-f) can be obtained by N-alkylation of an amine of formula (VI) intermediate product of the formula (VII), where W3provides a suitable reaction removable group, such as, for example, halogen.

< / BR>
The compounds of formula (I) can be converted into each other using known methods of conversion of functional groups.

The compounds of formula (I) can also be converted into the corresponding N-oxide forms by the following known methods of converting trivalent nitrogen into its N-oxide form. Y is (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as, for example, benzonorbornadiene or halogensubstituted benzonorbornadiene, for example, 3-chlorobenzalmalononitrile, phenoxyalkanoic acid, for example, peroxyoctanoic acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol, etc., hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of these solvents.

A number of intermediates and starting materials are commercially available or are known compounds which can be obtained using known methods.

For example, some of the intermediate compounds of formula (III) and obtaining them are described in EP-A-0 037 265, EP-A-0 053 070, EP-A-0 196 132 and EP-A-0 378 255.

Intermediate compounds of formula (II) can be obtained by methods described C. Cattanach et al. (J. Chem. Soc (C), 1971, 53-60); Kartashova T (Chem. Geechee intermediate compounds of formula (II) shown in figure 1, listed at the end of the description.

Stage and can be performed similarly to the method described in Tetrahedron (1981), 37, 979-982. Benzofuran obtained in stage C, was used as intermediates in the US 4 210 655. The following stages of the reaction are similar to the methods described in US 3 752 820.

Alternatively, intermediate compounds of formula (II) can be obtained at stages of the reaction depicted in scheme 2, is given at the end of the description.

Stage and can be performed similarly to the method described in Heterocycles(1994), 39(1), 371-380. Stage b can be performed similarly to the method described in J. Med. Chem. (1986), 29(9), 1643-1650. The following stages of the reaction can be performed similarly to the methods described in J. Heterocycl. Chem. (1979), 16, 1321.

Some of the compounds of formula (I) and some of the intermediate compounds in the present invention contain at least one asymmetric carbon atom. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained using known methods. For example, diastereoisomers can be separated using physical methods such as selective crystallization or chromatography, for example, countercurrent distribution, fluid is first mentioned racemic mixtures with suitable separating agents, such as, for example, chiral acids, mixtures diastereoisomeric salts or compounds; then the physical separation of these mixtures diastereoisomeric salts or compounds, for example, by selective crystallization or chromatography, for example, liquid chromatography, etc. methods; and, finally, to transform these separated diastereoisomeric salts or compounds into the corresponding enantiomers.

Pure stereochemical isomeric forms of the compounds of formula (I) can also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting materials, provided that these reactions proceed in a stereospecific manner. Pure and mixed stereochemical isomeric forms of the compounds of formula (I) are also included in the scope of the present invention.

The compounds of formula (I), their N-oxide forms, the pharmaceutically acceptable salt of accession and stereochemical isomeric form block presynaptic AG receptors on Central noradrenergic neurons, increasing, thus, the release of norepinephrine. Blocking these receptors to suppress or relieve a variety of symptoms related is to use these compounds are depression, cognitive disorders, Parkinson's disease, diabetes, sexual dysfunction and impotence, and increased intraocular pressure.

It is also shown that blocking2receptors in the Central nervous system increases the release of serotonin, which can also contribute to the treatment of depression (Maura et al., 1992, Naunyn-Schmiedeberg''s Arch. Pharmacol., 345: 410-416).

It is also shown that blocking2receptors using these compounds induces an increase in extracellular 3,4-dehydrophenylalanine acid, which is a metabolite of dopamine and norepinephrine.

From the point of view of the suitability of the compounds of the present invention for treatment of diseases associated with deficiency of norepinephrine in the Central nervous system, in particular, depression and Parkinson's disease, the present invention relates to a method of treating warm-blooded animals suffering from these diseases, in particular, depression and Parkinson's disease; this method includes systemic injection of a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt accession.

These compounds are also potentially suitable for Les acetylcholine (Tellez et al., 1997, J. Neurochem. 68:778-785).

In General, it is expected that therapeutically effective daily amount of approximately from 0.01 to 4 mg/kg body weight.

The present invention thus also relates to compounds of formula (I) defined above, intended for use as a drug. In addition, the present invention relates also to the use of compounds of formula (I) for drugs for treatment of depression and Parkinson's disease.

Research devoted to the study of signal transduction receptors and binding receptors, both ex vivo and in vitro, and the ability to reverse clonidine-induced reduction of the induced electric irritation of the release of noradrenaline from the cerebral cortex of rabbits, can be used to assess the antagonism of these compounds against2-adrenergic receptors. As indicators of Central blockade2-adrenergic receptors in vivo can be used reversal of inhibition reflex straightening observed in rats after intravenous injection of xylazine, and inhibition of the tremor induced by reserpine.

Test Domodevo of the invention were able to enhance the competitive behavior of subordinate individuals.

These compounds also demonstrate the effect on the intestines; they reversiruyut Antidiarrhoeal effect of clonidine and stimulate the release of faeces from fed rats. In dogs, they are able to speed up the start-induced magnesium diarrhea, and in the test for gastric emptying they have the ability to reverse the delay evacuation of gastric contents, induced 2-agonist by lidamycin. Thus, these compounds are suitable for the treatment of diseases associated with disorders of intestinal peristalsis.

Compounds of the present invention also have the ability to quickly penetrate into the Central nervous system.

For convenience, the introduction of these compounds can be placed in different pharmaceutical compositions comprising pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of the compounds of formula (I). For the manufacture of pharmaceutical compositions of the present invention an effective amount of a specific compound in the form of a salt of accession or in the form of free acid or base as the active ingredient, together with a homogeneous mixture of pharmaceutically receiving the drug for a particular route of administration. These pharmaceutical compositions is preferably made in the form of standard dosage forms, convenient, preferably, for oral, percutaneous or parenteral administration. For example, in the manufacture of a composition in the form of dosage forms for oral administration can be any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols, etc., in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricating agents, binding agents, disintegrating agents, etc., in the case of manufacturing powders, pills, capsules and tablets. Because of the ease of use of tablets and capsules represent the most advantageous dosage form for oral administration, for the manufacture of which, of course, are for solid pharmaceutical carriers. For the manufacture of compositions for parenteral administration the carrier typically includes sterile water, at least most of it, although you can include other ingredients, for example, agents to improve the solubility. Injectable solutions, for example, can be produced with the inclusion Asia the compounds of formula (I), it is possible to make oil-based, providing a prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cotton seed, corn oil, soybean oil, synthetic esters of glycerol and long chain fatty acids and mixtures of these and other oils. It is possible to make a suspension for injection, in which you can use the appropriate liquid carriers, suspendresume agents, etc. In the compositions suitable for percutaneous administration, the carrier optionally comprises agents that enhance penetration through the skin, and/or suitable irrigated agent, optionally in combination with suitable auxiliary substances of different nature in minor proportions, which have no significant adverse effects on the skin. These excipients can facilitate the application of the drug on the skin and/or can facilitate making the desired compositions. These compositions can be administered in a number of ways, for example, in the form of a percutaneous patch, in the form of application or ointments. Obviously, for the manufacture of aqueous compositions more convenient salt accession (I) because of their higher rastvorimogo to produce the above pharmaceutical composition in dosage forms, for ease of use, and provide a standard dosages. Dosage form specified in the description and the claims refers to physically discrete units suitable as standard doses, each of which contains a predetermined quantity of active ingredient calculated to provide the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including tablets with notches and coated tablet), capsules, pills, sachets of powder, pills, solutions or suspensions for injection, solutions with indication of reception tea or tablespoons, and containing them in a certain amount of packaging.

The following examples are intended to illustrate the present invention.

Experimental part

Next "CT" stand at room temperature, "THF" is tetrahydrofuran, "DMF" - N,N-dimethylformamide and DIPA" - diisopropyl ether.

A. the production of intermediate compounds

Example A1

A mixture of hydrochloride On-phenylhydroxylamine (1:1) (of 0.625 mol) hydrochloride and 4,4-piperidinedione (1:1) (0,682 mol) in 2-propanol (615 ml) peremeshivaete boiling under reflux. The reaction mixture was stirred and heated under reflux for 3 hours, then cooled to room temperature. The precipitate was filtered, washed, DIPE and dried. This faction was led out of the water (1600 ml). The desired compound crystallized with stirring. The precipitate was filtered off, washed with 2-propanol and DIPE, and then dried to obtain 84 g (64%) of the hydrochloride 1,2,3,4-tetrahydrothieno [3,2-e] pyridine (1: 1) (intermediate compound 1).

Example A2

1,4-Dioxa-8 azaspiro[4,5] decane (0,12 ml) was added dropwise to a mixture of the hydrochloride of O-(4-forfinal)hydroxylamine (1: 1) (0.1 mol) in a mixture of Hcl and 1,1-oxybisethane (150 ml). The reaction mixture was stirred and heated under reflux for 4 hours, and then cooled. The precipitate was filtered and dried, then recrystallized from water to obtain 10 g (43,9%) of the hydrochloride 1,2,3,4-tetrahydro-8-Formentera[3,2-C] pyridine (intermediate compound 2; so pl. >300oC).

Example A3

a) 1,2,3,4-Tetrahydro-2-methyl-6-nitrobenzoate[3,2-C]pyridine (0,0224 mol), obtained according to the method described in J. Chem. Sc. (C), 1971, 53-60, was dissolved in 1,2-dichloroethane (40 ml) and cooled to 0oC. At this temperature dobavlyali within 2 hours. 1,2-Dichloroethane is evaporated. The mixture was dissolved in methanol, was stirred and heated under reflux for 2 hours, then filtered. And the filtrate, and the crystals was treated with 2n. PA2CO3and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent evaporated to obtain 1.5 g of 1,2,3,4-tetrahydro-6-nitrobenzoate[3,2-C]pyridine (intermediate compound 4).

b) a Mixture of 1,2,3,4-tetrahydro-2-methyl-6-nitrobenzoate[3,2-C] pyridine (0,0215 mol) and triethylamine (2 g) in THF (200 ml) was first made using palladium on coal as a catalyst 10% (2 g) in the presence of thiophene 4% (2 ml). After absorption of H2(3 equivalent), the catalyst was filtered and the filtrate evaporated with the receipt of 4.2 g of 1,2,3,4-tetrahydro-6-amino-2-methylbenzofuran[3,2-e]pyridine (intermediate compound 7).

(C) a Mixture of intermediate compound (7) (0,0100 mol) in Hcl (2 ml) was diazotisable when -5oUsing NaNO2(0,0105 mol) in water (1.2 ml) for 30 minutes the Solution was stirred for 30 min at -5ooWith, then was cooled to 20oC. After dilution with water was added an excess of 40% solution TO2CO3and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated to obtain 1.7 g (78%) of 1,2,3,4-tetrahydro-6-chloro-2-methylbenzofuran[3,2-C]pyridine (intermediate compound 8).

Example A4

a) a Mixture of intermediate (1) (0.03 mol), chloroacetonitrile (0.04 mol), potassium iodide (0.1 g) and Na2CO3(5 g) in 4-methyl-2-pentanone (180 ml) was stirred and heated under reflux for 3 hours. The warm mixture was filtered and the filtrate evaporated. The residue was purified on silica gel on a glass filter (eluent: CH2CL2/CH3HE/NH395/5). The desired fractions were collected and the solvent evaporated. The residue was led from DIPE/petroleum ether 1/1. The precipitate was filtered and dried to obtain 5,74 g (90%) of 3,4-dihydrobenzofuran[3,2-C]pyridine-2(1H)-acetonitrile (intermediate compound 10; so pl. 78oC).

b) a Mixture of intermediate (10) (0,027 mol) in CH3HE/NH3(200 ml) was first made by using as a catalyst of Raney Nickel (2 g) in the presence of thiophene 4% (1 ml). After absorption) 1,2,3,4-tetrahydro-2-(aminoethyl)benzofuro[3,2-C]pyridine (intermediate compound 12).

Example A5

a) a Mixture of intermediate (1) (0.03 mol), ethyl(5-chloropentyl)carbamate (0.04 mol), potassium iodide (0.1 g) and PA2CO3(5.7 g) in toluene (250 ml) was stirred and heated under reflux overnight. The reaction mixture was cooled, stirred in water (200 ml) and the layers were separated. The organic phase is evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/CH3OH 95/5). Pure fractions were collected and the solvent evaporated to obtain 7 g of ethyl[5-(3,4-dihydrobenzofuran[3,2-C]pyridine-2 (1H)pentyl] carbamate (intermediate compound 15).

b) a Mixture of intermediate (15) (0,021 mol) and potassium hydroxide (12 g) in 2-propanol (120 ml) was stirred and heated under reflux for 6 hours. The solvent is evaporated. The residue was distributed between CH2Cl2and water. The organic layer was separated, dried, filtered and the solvent evaporated to obtain 4 g of 3,4-dihydrobenzofuran[3,2-C]pyridine-2(1H)-pentamine (intermediate compound 16).

Example A6

a) a Mixture of 3-hydroxyethylpiperazine (0.6 mol) and Na2CO3(130 g) in l3(600 ml) was stirred at 10oC. was added dropwise eilhart the room temperature, and the reaction mixture was stirred over night. Was added water (500 ml). The organic layer was separated, washed with water, dried, filtered and the solvent evaporated to obtain 110 g (98%) (a)-ethyl 3-(hydroxymethyl)-1-piperidinecarboxylate (intermediate compound 17).

b) a Solution of methylphenylsulfonyl (0,79 mol) in pyridine (200 ml) was added dropwise to a solution of intermediate 17 (0.4 mol) in pyridine (150 ml), was stirred in 10oC. the Mixture was stirred until then, until it has reached room temperature, and the reaction mixture was stirred over night. Under stirring the mixture was poured into water (1000 ml) and was extracted with isobutyl ketone. The separated organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was led from a mixture of diisopropyl ether and petroleum ether. The precipitate was filtered and dried to obtain 96 g (70.3 per cent) (a)-ethyl 3-[[[(4-were) sulfonyl] oxy] methyl] -1-piperidinecarboxylate (intermediate compound 18).

c) a Mixture of intermediate (18) (0,0088 mol), the free base of intermediate compound (1) (0,0080 mol) and Na2CO3(to 0.016 mol) in DMF (25 ml) was stirred and the current is distributed between CH2Cl2and 50% aqueous NaCl solution. The layers were separated. The aqueous layer was extracted three times CH2CL2. The combined organic layers were dried, filtered and the solvent evaporated. The residue was purified by HPLC on silica gel (eluent: CH2CL2/CH3HE 95/5). Pure fractions were collected and the solvent evaporated to obtain a 1.5 (55%) g of ethyl 4-[[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl] methyl] -1-piperidinecarboxylate (intermediate compound 19).

The following intermediate compounds are presented in table. 1 and 2, were obtained analogously to one of the examples above.

C. obtain the final compounds

Example B1

a) a Mixture of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-it (0,0050 mol), obtained in accordance with the methods described in EP 0 070 053, free base of intermediate compounds (1) (0,0040 mol), Na2CO3(0,008 mol) and potassium iodide (0,0040 mol) in 4-methyl-2-pentanone (8 ml) was stirred and heated under reflux overnight. The reaction mixture was cooled. Added a 50% aqueous solution of NaCI and CH2Cl2. The phases were separated. The aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried, Fel (eluent: C2H5HE/CH2Cl25/95). The desired fractions were collected and the solvent evaporated. The residue was ground and treated by ultrasound in DIPE, then was filtered and dried to obtain 0.9 g(63%) 3-[2-[3,4-dihydrobenzofuran[3,2-C]pyridine-2(1H)-yl]ethyl] -2-methyl-4H-pyrido[1,2-a]pyrimidine-4-she (compound 3; so pl. 186,2oC).

b) 6-[[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a] pyrimidine-5-he (compound 5) was obtained similarly to the method described in example VI, but to the reaction mixture was added potassium iodide.

c) a Mixture of intermediate (1) (0,015 mol) and triethylamine (4 g) in 4-methyl-2-pentanone (150 ml) was stirred for 5 minutes was Added 9-methoxy-2-methyl-3-[2-[(methylsulphonyl)oxy] ethyl] -4H-pyrido[1,2-a] pyrimidine-4-one obtained as described in W095/14691, and the resulting reaction mixture was stirred and heated under reflux for 6 hours. The warm mixture was filtered and the filtrate was stirred with water (100 ml). The organic layer was separated, dried, filtered and the solvent evaporated. The residue was led from DIPE and a small amount of CH3The JV. This product was filtered and dried. This fraction was purified by column chromatography n is Lee. The residue was led from DIPE. The precipitate was filtered and dried to obtain 0.6 g of 3-[2-[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl] ethyl]-9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-she (compound 65; T. pl. 151oC).

Example B2

A mixture of intermediate (12) (0,0116 mol), 2-chlorobenzothiazole (0,0118 mol) and NaHCO3(2 g) in 2-ethoxyethanol (45 ml) was stirred and heated under reflux for 2 hours. The reaction mixture was cooled and added with stirring, water (45 ml). The solid was filtered with suction, washed with water, stirred in DIPE, was filtered and dried. This fraction was dissolved in a small amount of methanol and transferred in (E)-2-butenedioate acid (1:1) under stirring and heating. This mixture was left to cool to room temperature under stirring and the resulting precipitate was filtered and dried to obtain 3.4 g (63%) of N-2-benzothiazole-3,4-dihydrobenzofuran[3,2-C]pyridine-2(1H)-ethanamine (E)-2-butenedioate (1:1) (compound 51; T. pl. 210oC).

Example B3

Potassium hydroxide (0,088 mol) was added to a hot solution of intermediate (19) (0,0044 mol) in 2-propanol (50 ml) and the resulting reaction mixture was stirred and heated to about the Cl2. The layers were separated. The aqueous phase was extracted three times CH2Cl2. The combined organic phase was dried, filtered and the solvent was removed. The residue was purified by column flash chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH395/5). The desired fractions were collected and the solvent evaporated. The residue was dissolved in l3(15 ml). Was added triethylamine (0,726 g). Added 4-methylbenzoate (0,0075 mol) and the reaction mixture was stirred for one hour. Added 50% aqueous NaOH solution. The layers were separated. The aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried, filtered and the solvent evaporated. The residue was purified by column flash chromatography on silica gel (eluent: CH2CL2/CH3HE 97/3). Pure fractions were collected and the solvent evaporated. The residue was dried to obtain 1.1 g(64%) 4-[(3,4-dihydrobenzofuran[3,2-C]pyridine-2(1H)-yl)methyl] -1-(4-methylbenzoyl)piperidine (compound 58; so pl. 140,3oC).

Example B4

Connection (3) (0,0083 mol) was dissolved in heated to the boiling point under reflux with 2-propanol (80 ml). Was added dropwise a mixture of Hcl and 2-propanol to peremeshivaemogo was filtered and dried to obtain 3.2 g of 3-[2-(3,4-dihydrobenzofuran[3,2-C] pyridine-2 (1H)-yl) ethyl]-2-methyl - 4H-pyrido [1,2-a]pyrimidine-4-she (compound 43).

The following compounds are presented in table. 3 and 4, were obtained analogously to one of the examples above.

In table. 5 are listed as experimental (column "exp") and theoretical (column "theoretical" values of elemental analysis for carbon, hydrogen and nitrogen for the compounds obtained in the experimental part, above.

C. Pharmacological examples

Example C1: Binding affinity against2receptors in vitro

The interaction of compounds of formula (I) and2receptors evaluated in experiments linking radioligand in vitro.

Usually, radioligand with high binding affinity to a specific receptor at low concentrations, incubated with the sample preparation tissue enriched with a particular receptor, or with a preparation of cells expressing the cloned receptors person in the buffer medium. During incubation, radioligand binds to the receptor. Upon reaching equilibrium binding was separated radioactivity associated with the receptor from unbound radioactivity, and counted the radioactivity associated with the receptor. The interaction of the tested compounds and receptors evaluated in experimntal test compound in various concentrations. Linking radioligand inhibited by the test compound is proportional to its binding affinity and concentration.

Radioligands that was used to bind with the2Areceptors were3H-rauwolscine, and drug receptors in cells of the Chinese hamster ovary (Cho) expressing the cloned human2-receptors. Connection rooms 1-8, 10, 13-15, 17, 18, 23-25, 27-31, 33, 34, 36-38, 48, 49, 52, 53, 55, 56, 60, 62, 63, 65 and 66 caused inhibition of more than 50% at a test concentration of 10-8M or less; in connection rooms 9, 11, 12, 16, 19, 20, 22, 26, 35, 41, 44, 51, 57, 58, 59 and 64 caused inhibition of more than 50% at a test concentration of 10-8up to 10-6M, and the rest were caused inhibition less than 50% at a test concentration of 10-6M

Radioligands that was used to bind with the2Breceptors were3H-rauwolscine, and drug receptors - cells SNO expressing cloned human2B-receptors. Connection rooms 1-8, 10, 13-15, 23, 25-28, 30, 31, 33, 34, 38-40, 48-50, 52, 53, 55, 56, 62, 63 and 66 caused inhibition of more than 50% at a test concentration of 10-8M or less; in connection rooms 9, 11, 12, 16-19, 24, 29, 35-37P> M, and the rest were caused inhibition less than 50% at a test concentration of 10-6M

Radioligands that was used to bind with the2Creceptors were 3H-rauwolscine, and drug receptors - cells SNO expressing cloned human2C-receptors. Connection rooms 1-6, 8, 10, 13, 14, 23, 25, 27-31, 33, 34, 36-40, 48, 50, 52, 53, 55, 58, 62, 63, 65 and 66 caused inhibition of more than 50% at a test concentration of 10-8M or less; in connection rooms 7, 9, 11, 12, 15-19, 22, 24, 26, 35, 41, 44, 49, 51, 56, 57, 59-61 and 64 caused inhibition of more than 50% at a test concentration of 10-8up to 10-6M, and the rest were caused inhibition less than 50% at a test concentration of 10-6M

Example C2: Xylazine-induced inhibition of straightening reflex in rats

This test is based on the fact that antagonists2-adrenoreceptor Central action reversiruyut oppression of straightening reflex induced by intravenous injection2the agonist xylazine. An hour before the injection of xylazine (15 mg/kg) to male rats (200-250 g) was pre-entered test connection (oral p/o) or subcutaneously (s/C) or only the solvent. In rats, the dividing of time up to 120 min after injection. The criterion for activity of the test compounds was no inhibition of reflex straightening. The lowest active dose (PAD) of the tested compounds against antagonism to the drug was determined as the lowest tested dose at which at least 66% of the experimental animals did not show inhibition of reflex straightening. Table. 6 results the results of this study these compounds.

D. Examples of songs

"Active ingredient" (AI) specified in these examples relates to a compound of formula (I), its pharmaceutically acceptable salt or accession or stereochemical isomeric form.

Example D1: Capsules

20 g AI, 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate were intensively mixed. The mixture was then filled with 1000 suitable hard gelatin capsules, 20 mg AI each.

Example P2: coated tablet

Manufacturing core tablets

A mixture of 100 g AI, 570 g lactose and 200 g starch were thoroughly stirred, and then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone approximately 200 ml of water. Wet powder mixture procainamidesee oil. All together thoroughly mixed and extruded into pellets, with taking tablets, 10 mg of active ingredient each.

Shell

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene Glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the previous, and then added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye together and homogenized. Core tablets were coated mixture in the apparatus for coating pills.

Example D3: Solution for oral administration

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate was dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 g of 2,3-dihydroxybutanedioate acid, and then 20 g AI. The latter solution was combined with the remaining part of the previous solution, and thereto were added to 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of saccharin sodium was dissolved in 0.5 l of water was added 2 ml of raspberry and 2 ml krizovany essences. The latter solution was added to the previous, is that one teaspoon (5 ml). The resulting solution was filling appropriate containers.

Example D4: Solution for injection

1.8 g of methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxybenzoate was dissolved in approximately 0.5 l of boiling water for injection. After cooling to approximately the 50oWith added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of AI. The solution was cooled to room temperature and added to water for injection to a volume of 1 l with obtaining a solution for injection containing 4 mg/ml AI. This solution was sterilized by filtration and filled them sterile containers.

1. Derivatives of 1,2,3,4-tetrahydrothieno[3,2-C]pyridine of formula (I)

< / BR>
N-oxide form, or a pharmaceutically acceptable salt accession or their stereochemical isomeric form,

where each R1independently represents hydrogen, halogen, C1-6alkyl, C1-4alkoxy or nitro-group;

Alk represents a C1-6alcander;

n is 1 or 2;

D represents 1 - or 2-benzimidazolyl, 2 (3H)benzoxazolone-3-yl or a radical of formula (a), (b), (C), (d), (e), (f), (g), (h)

< / BR>
< / BR>
< / BR>
< / BR>
where each X represents S;

R2represents C1-6alkyl, aryl or arils1-6alkyl;

R each, independently, represents hydrogen or C1-6alkyl;

R9represents aryl

or R3and R4taken together may form a bivalent radical R3-R4formula (a-2) or (a-5)

-CH2-CH2-CH2-CH2- (a-2)

-CH=CH-CH=CH- (a-5)

where one or two hydrogen atoms of these radicals are each, independently, may be replaced by halogen, C1-6the alkyl, aryls1-6the alkyl, trifluoromethyl, amino, hydroxy or C1-6alkyloxy, or where possible, two genialnyh hydrogen atom may be replaced by arils1-6alkylidene; or R3-R4-can also have the formula (a-6), (7), (8), (a-11) or (a-14)

-S-CH2-CH2- (and-6)

-S-CH2-CH2-CH2- (a-7)

-S-CH=CH- (a-8)

-NH-CH=CH- (a-11)

-CH=CH-O- (a-14)

where from one to three hydrogen atoms of these radicals, each independently, may be replaced by C1-6the alkyl and aryl represents phenyl or phenyl substituted C1-6the alkyl.

2. Connection on p. 1, in which D is 1-benzimidazolyl, 2 (3H)benzoxazolone-3-yl or D is a radical of formula (a), where R3represents C1-6alkylthio and R4represents C1-61-6the alkyl, aryls1-6the alkyl, trifluoromethyl, amino, hydroxy, C1-6alkyloxy; or where possible, two genialnyh hydrogen atom may be replaced by arils1-6alkylidene; or a bivalent radical of formula (a-6), (7), (8), (a-11) or (14), where one or possibly two or three hydrogen atoms of these radicals, each independently, may be replaced by C1-6by alkyl; or D is a radical of formula (b), where R5and R6submit C1-6alkyl; or D is a radical of formula (C), where R7represents hydrogen; or D is a radical of formula (d), where R8represents hydrogen or C1-6alkyl; or D is a radical of the formula (e), where R9represents aryl; or D is a radical of formula (f), where X is S, and R10represents hydrogen; or D is a radical of formula (g), where X is S, and R11represents C1-6alkyl.

3. Connection under item 1 or 2, in which n is 1 and R1represents hydrogen, chlorine, fluorine, methyl or nitro, or n is 2 and R1represents methoxy.

4. The compound according to any one of paragraphs.1-3, in which R1is hydrogen and D before the uly (a-2) or (a-5), where one or two hydrogen atoms each independently may be replaced by halogen, stands, methoxy, arylmethyl, trifluoromethyl, amino or hydroxy, or in which two genialnyh hydrogen atom replaced by arylmethylene, or R3and R4taken together form a bivalent radical of formula (a-6), (7), (8), (a-11) or (14), where one or possibly two or three hydrogen atoms are replaced by stands.

5. Connection on p. 1, where the compound is 3-[2-[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl] ethyl]-2-methyl-4H-pyrido [1,2-a]pyrimidine-4-one;

6-[[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl] ethyl] -7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-he;

6-[[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl] ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine-5-he;

3-[2-[3,4-dihydrobenzofuran[3,2-C] pyridine-2(1H)-yl] ethyl] -2,7-dimethyl-4H-pyrido[1,2-a] pyrimidine-4-one; its N-oxide and pharmaceutically acceptable salt accession or their stereoisomeric form.

6. The compound according to any one of paragraphs.1-5, suitable for the preparation of compositions having antagonistic activity against Central-adrenergic receptors.

7. The compound according to any one of paragraphs.1-5, suitable for the production of compositions for the treatment of diseases, assotsiirovannaya antagonistic activity against Central-adrenergic receptors, containing a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of paragraphs.1-5.

9. The composition is suitable for treatment of diseases associated with a deficiency of norepinephrine in the Central or peripheral nervous system, containing a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of paragraphs.1-5.

10. A method of obtaining a connection on p. 1, including N-alkylation derivative of 1,2,3,4-tetrahydrobenzene[3,2-C]pyridine of formula (II)

< / BR>
alkylating reagent of formula (III)

D-Alk-W1(III)

where W1is the appropriate reaction of the deleted group, a D, Alk, R1and n are defined in paragraph 1,

and, if desired, converting compounds of formula (I) into each other using well-known transformations, and further, if desired, converting compounds of formula (I) into a therapeutically active non-toxic salt accession acids by treatment with an acid, or into a therapeutically active non-toxic salt accession bases by treatment with a base, or conversely, converting a salt of joining cikolata by treatment with an acid and, if desirable, obtaining their stereoisomeric forms or N-oxide.

11. A method of obtaining a connection on p. 1, including the removal of protection N-protected intermediate compound (IV)

< / BR>
and subsequent N-acylation of the obtained intermediate acyl derivative of formula (V)

< / BR>
where P represents a protective group, W2is the appropriate reaction of the deleted group, a R1, R9, Alk and n are defined in paragraph 1, in the resulting compound of the formula (1-e)

and, if desired, converting compounds of formula (I) into each other using well-known transformations, and further, if desired, converting compounds of formula (I) into a therapeutically active non-toxic salt accession acids by treatment with an acid, or into a therapeutically active non-toxic salt accession bases by treatment with a base, or conversely, converting a salt accession acid free base by treatment with alkali, or converting a salt of attaching the base to the free acid by treatment with an acid and, if desired, obtaining their stereoisomeric forms or N-oxide.

12. A method of obtaining a connection on p. 1, including N-alkylation by reaction of the deleted group, and X, Alk, R1, R10and n are defined in paragraph 1, in the resulting compound of the formula (I-f),

and, if desired, converting compounds of formula (I) into each other using well-known transformations, and further, if desired, converting compounds of formula (I) into a therapeutically active non-toxic salt accession acids by treatment with an acid, or into a therapeutically active non-toxic salt accession bases by treatment with a base, or conversely, converting a salt accession acid free base by treatment with alkali, or converting a salt of attaching the base to the free acid by treatment with an acid and, if desired, obtaining their stereoisomeric forms or N-oxide.

 

Same patents:

The invention relates to new derivatives of 5H-thiazole[3,2-a]pyrimidine of the General formula I, where R1means (ness.)alkyl or benzyl; R2means (ness.) alkyl, (ness.)alkoxygroup, -O(CH2)nN(R13)(R14or-N(R15)(CH2)nN(R13)(R14); R3-R14each denotes hydrogen, halogen, (NISS

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

Ar denotes phenyl or naphthyl, unsubstituted or one-, two - or three-fold substituted with H, Gal, Q, alkenyl with the number of C-atoms up to 6, Ph, OPh, NO2, NR4R5, NHCOR4, CF3, OCF3CN, OR4, COOR4, (CH2)nCOOR4, (CH2)nNR4R5, -N=C=O or NHCONR4R5phenyl or naphthyl;

R1, R2, R3each independently from each other, are absent or represent H, Gal, Q, CF3, NO2, NR4R5, CN, COOR4or CHCOR4;

R4, R5each independently of one another denote H or Q, or together also denote-CH2-(CH2)N-CH2-;

Q denotes alkyl with 1-6 C-atoms;

Ph denotes phenyl;

X denotes O or S;

Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

and their salts, except 4-methyl-N-(2,1,3-benzothiadiazole - 5-yl)benzosulfimide, 4-nitro-N-(2,1,3-benzothiadiazole-5-yl)- benzosulfimide and 4-amino-N-(2,1,3-benzothiadiazole-5-yl)- benzolsulfonat

The invention relates to the field of production of new heterocyclic O-dicarbonitriles, which can be used to achieve different hexatriene, useful as active media of liquid and solid lasers, scintillators, for the transformation of shortwave radiation in the long wavelength in the transmission of information through fiber-optic communication lines and so on

The invention relates to medicine and relates to a method of inhibiting tyrosine kinase receptor, epidermal growth factor, for example, Erb-b2, Erb-b3, or Erb-b4, by introducing to a mammal in need, an effective amount of nitrogen-containing heterocyclic compounds, which is that as the nitrogen-containing heterocyclic compounds used as a compound of formula I, where R1-R9are specified in the claims value, or its pharmaceutically acceptable salt, or hydrate, thereof the pharmaceutical composition and the contraceptive composition based on them

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula II, where R1, R2are primocane C1-6alkyl group; R4represents unsubstituted phenyl; R5and R8represent hydrogen; R6represents methoxy or bromo; R7arepresents methoxy, hydroxy or trifluoromethyl; R9and R10represent hydrogen, salts, solvate or physiologically functional derivatives, and method of production thereof

The invention relates to new benzoxazine and piridokshinom compounds of formula I, where part of the Q - condensed phenyl, or condensed pyridyl; Z1is hydrogen, halogen, C1-C6alkyl, phenyl, nitro, sulfonylamino or trifluoromethyl; Z2is hydrogen or halogen; X is hydrogen or oxygen; And - C1-C6-alkyl, C1-C6-alkylaryl or C1-C6-Alkylglucoside, where aryl and heterocyclyl described in the claims, n = 0 to 3; Y is the portion described in the claims, and their pharmaceutically acceptable salts, esters and proletarienne forms

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

Ar denotes phenyl or naphthyl, unsubstituted or one-, two - or three-fold substituted with H, Gal, Q, alkenyl with the number of C-atoms up to 6, Ph, OPh, NO2, NR4R5, NHCOR4, CF3, OCF3CN, OR4, COOR4, (CH2)nCOOR4, (CH2)nNR4R5, -N=C=O or NHCONR4R5phenyl or naphthyl;

R1, R2, R3each independently from each other, are absent or represent H, Gal, Q, CF3, NO2, NR4R5, CN, COOR4or CHCOR4;

R4, R5each independently of one another denote H or Q, or together also denote-CH2-(CH2)N-CH2-;

Q denotes alkyl with 1-6 C-atoms;

Ph denotes phenyl;

X denotes O or S;

Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

and their salts, except 4-methyl-N-(2,1,3-benzothiadiazole - 5-yl)benzosulfimide, 4-nitro-N-(2,1,3-benzothiadiazole-5-yl)- benzosulfimide and 4-amino-N-(2,1,3-benzothiadiazole-5-yl)- benzolsulfonat

The invention relates to compounds of the formula I, their pharmaceutically acceptable salts and stereoisomeric forms, where R is hydrogen or C1-6-alkyl; R2is hydrogen; C1-6-alkyl; trihalomethanes; C1-6-alkyl, substituted carboxyla,1-6-alkylcarboxylic,1-6-allyloxycarbonyl, or R1and R2taken together with the nitrogen atom to which they are attached, may form a ring morpholinyl or optionally substituted heterocyclic radical; R3- R10each independently represents hydrogen; R8, R9independently represent hydrogen or halogen; R11and R12is hydrogen; n= 1, 2, 3, 4, 5 or 6; X Is O, S, S(=O)

The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

The invention relates to new chemical compounds with valuable biological properties, in particular to derive hinolan and naphthyridinone acids with antibacterial activity, as well as to the isoindole derivative as starting compounds for obtaining the derivatives hinolan and naphthyridinone acid

The invention relates to new heterocyclic compounds with biological activity, more specifically, to the derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or HIV activity, method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it and the method of treating mammals infected with HIV
Up!