Isoquinoline and benzo[h]isoquinoline derivatives, their obtaining and their application in therapy as antagonists of histamine h3 receptor

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of formula I in which cycle A represents unsaturated carbocycle with double bonds, which is selected from phenyl or naphtyl; 1 can take value from 1 to 3; m can take value 0, 2 or 3; n can take value 0 or 2; R1 represents a hydrogen atom, (C1-3)alkyl group; R2 represents(C1-6)alkyl group, which is possibly substituted with substituent, selected from C6-cycloalkyl, monocyclic heteroaryl, selected from thiophene, aryl group, selected from phenyl, in form of base or salt of bonding with an acid. Invention also relates to pharmaceutical composition, based on formula I compound, to application of formula I compound for obtaining medication, to method of obtaining formula I compound and to application of formula compound for obtaining formula 1 compound.

EFFECT: obtained are novel isoquinoline and benzo[h]isoquinoline derivatives, possessing properties of antagonists of histamine type H3 receptor.

9 cl, 1 tbl, 6 ex

 

The object of the present invention are ethers, derivatives of tetrahydroisoquinoline, tetrahydrobenzo[h]isoquinoline, method of their production and their use in therapy.

In WO 02/076925 described receptor antagonists N3histamine. Some of these compounds are ethers derived isoquinolines or benzothiophene, with which is connected a linear or cyclic alkylamines followed.

The purpose of the applicants are new compounds modulating the activity of receptor H3histamine.

Thus, the first object of the present invention are new compounds of formula I

in which

denotes unsaturated carbocycle with double bonds, such as phenyl or naphthyl, and carbocycle possibly substituted by one or more substituents selected independently of one another from halogen atom, hydroxy, nitro group, cyano,

(C1-2)perhalogenated, (C1-3)alkyl or phenyl;

l can take values from 0 to 4;

m can take values from 0 to 3;

n can take values from 0 to 6;

(C)- l-, -(C)m (C)n represent independently of each group (Cx-z)alkylidene, possibly substituted by 1-4 substituents selected from halogen atom, hydroxy group, nitro, cyano, AMI is about, (C1-2)perhalogenated, (C1-3)alkyl or phenyl; and additionally, if l, m and/or n is 0,- ()0indicates the connection;

R1 denotes a hydrogen atom, (C1-3)alkyl group,

(C1-6)alkylsulphonyl, (C1-6)alkoxycarbonyl, which may be substituted, these groups (C1-3)alkyl, (C1-6)alkylsulphonyl,

(C1-6)alkoxycarbonyl, a halogen atom, a hydroxy group,

(C1-3)alkoxy, nitro, cyano, amino or aryl, such as benzyloxycarbonyl; and (C1-3)alkylaryl, such as benzyl or phenethyl, monocyclic heteroaryl, such as thienyl, furyl or pyrrolyl, or aryl, such as phenyl or naphthyl, aryl and heteroaryl groups possibly substituted by 1-4 substituents selected from halogen atom, hydroxy group, nitro, cyano, amino, (C1-3)monoalkylamines, (C2-6)dialkylamino, (C1-3)alkyl,

(C1-2)perhalogenated, (C1-3)halogenoalkane, (C1-3)alkoxy group or (C1-3)alkylidene;

R2 denotes a hydrogen atom, (C1-6)alkyl group, or

(C3-6)cycloalkyl group, possibly substituted by 1-4 substituents selected from halogen atom, hydroxy group, nitro, cyano, amino, (C1-3)monoalkylamines, (C2-6)dialkylamino,

(C1-2)perhalogenated, (C1-3)halogenoalkane, (C1-3)alkoxy,

p> (C3-6)cycloalkyl, monocyclic heteroaryl, such as thienyl, furyl or pyrrolyl, bicyclic heteroaryl, such as benzotriazolyl, or aryl group such as phenyl or naphthyl; aryl possibly substituted by 1-4 substituents selected from halogen atom, hydroxy group, nitro, cyano, amino,

(C1-3)monoalkylamines, (C2-6)dialkylamino, (C1-3)alkyl,

(C1-2)perhalogenated, (C1-3)halogenoalkane, (C1-3)alkoxy, or the group (C1-3)alkylidenes.

In the framework of the present invention is meant

Withx-zwhere x and z can take values from 0 to 6, carbon chain that may contain from x to z carbon atoms, however, if x is equal to 0, C0means a connection, for example, With1-6refers to a carbon chain that may contain from 1 to 6 carbon atoms; C0-6means a connection or a carbon chain that may contain from 1 to 6 carbon atoms;

the alkyl is a saturated aliphatic linear or branched chain; for example, (C1-6)alkyl refers to saturated linear or branched carbon chain with 1-6 carbon atoms, specifically, methyl radical, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.;

the term (Cx-z)alkyliden indicates (Withx-y)alkyl, linear or branched, vocality; the term (C2-8)allenylidene indicates (Withx-y)alkyl, unsaturated linear or branched, divalent;

(Cx-y)alkoxy group, alkyloxy with saturated aliphatic linear or branched chain, containing from x to y carbon atoms;

the halogen atom is fluorine, chlorine, bromine or iodine;

(C1-3)monoalkylamines - monoamino, substituted (C1-3)alkyl group;

(C2-6)dialkylamino - amino, disubstituted two

(C1-3)alkyl groups, the same or different;

(C1-2)perhalogenated - (C1-2)alkyl group in which all hydrogen atoms are substituted by halogen atoms;

(C1-3)halogenated -(C1-3)alkyl group in which at least one hydrogen atom substituted by a halogen atom.

The compounds of formula I can contain one or more asymmetric carbon atoms. Thus, they can be in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as mixtures thereof, including racemic mixtures, belong to the invention.

Compounds of General formula I may be in the form of free bases or salts of joining with acids, which also belong to the invention. These salts of the present invention include salts with pharmaceutically acceptable acids, but also salts with inorganic or org the organic acids, which ensure appropriate separation or crystallization of the compounds of formula I. These salts can be obtained by methods known to the expert, for example, by reacting the compounds of formula I in the form of a base with an acid in an appropriate solvent, such as alcohol solution or an organic solvent, followed by the separation medium, containing, by evaporation of solvent or by filtration.

The compounds of formula I may also be in the form of a hydrate or of a solvate, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such a hydrate or solvate also belong to the invention.

The object of the present invention are compounds selected from the following subgroups considered separately or in combination, in which

denotes unsaturated carbocycle, such as phenyl or naphthyl, and carbocycle possibly substituted by one or two substituents selected independently of one another from halogen atom, hydroxy group, nitro, cyano, (C1-2)perhalogenated or (C1-3)alkyl;

l can take values 1, 2 or 3;

m can take values 0, 1 or 2;

n can take values 0, 1, 2 or 3;

(C)- l and(C)m - form together with the group-NR1 - aminocyclo associated atom ug is erode with the group-O-(C)n, such as azetidin, pyrrolidine, piperidine or azepine and/or

(C)- n - denotes -(C0-3)alkylidene, possibly substituted by 1-4 substituents selected from halogen atom, hydroxy group, nitro, cyano, amino, (C1-2)perhalogenated, however, if n is 0,- ()0indicates the connection;

R1 denotes a hydrogen atom, a group: (C1-3)alkyl,

(C1-6)alkylsulphonyl, (C1-6)alkoxycarbonyl; and (C1-3)alkylaryl, such as benzyl, heteroaryl, such as thienyl or furyl, aryl group such as phenyl or naphthyl; and aryl and heteroaryl groups can be substituted by 1-4 substituents selected from halogen atom, hydroxy group, cyano, amino,

(C1-3)monoalkylamines, (C1-3)alkyl, (C1-2)perhalogenated,

(C1-3)halogenoalkane, (C1-3)alkoxy or (C1-3)alkylidenes.

More specifically, if aminoacyl, part of which are

(C)- l-, -(C)m and-NR1-, and which is connected with a carbon atom with a group-O-(C)n-, selected from the following groups:

R2 denotes a hydrogen atom, (C1-3)alkyl or (C5-6)cycloalkyl, possibly substituted by 1-4 substituents selected from phenyl, monocyclic heteroaryl, such as thienyl, bicyclic heteroaryl, such as benzotriazolyl, (C3-6)cycloalkyl,

(C1-2)pergola is talkie, (C1-3)halogenoalkane or (C1-3)alkoxy; phenyl and heteroaryl possibly substituted by 1-4 substituents selected from halogen atom, hydroxy group, nitro, cyano, amino, (C1-3)monoalkylamines, (C2-6)dialkylamino, (C1-3)alkyl,

(C1-2)perhalogenated, (C1-3)halogenoalkane, (C1-3)alkoxy group or (C1-3)alkylidenes.

Another object of the invention are the following compounds and their pharmaceutically acceptable salts:

Connection 1: 7-{2-[1-methylpiperidin-2-yl]ethoxy}-2-propyl-1,2,3,4-tetrahydroisoquinoline;

Compound 2: 2-isobutyl-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

Compound 3: 2-(3-methylbutyl)-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

Compound 4: 7-[(1-mutilation-4-yl)oxy]-2-(3-methylbutyl)-1,2,3,4-tetrahydroisoquinoline;

Compound 5: (2-cyclohexylmethyl)-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

Compound 6: (2-cyclohexylmethyl)-7-{2-[(2R)-1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline;

Compound 7: (2-cyclohexylmethyl)-7-{2-[(2S)-1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline;

Compound 8: (2-cyclohexylmethyl)-7-[(1-mutilation-4-yl])oxy]-1,2,3,4-tetrahydroisoquinoline;

Compound 9: (2-cyclohexylmethyl)-7-[2(1-methylpiperidin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

Compound 10: 2-benzyl-7-[2(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

Compound 11: 2-benzyl-7-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydroisoquinoline;

The connection 12: 7-[(1-mutilation-4-yl)oxy]-2-(2-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline;

Compound 13: (2-cyclohexylethyl)-8-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline;

Compound 14: (2-cyclohexylethyl)-8-{2-[(2R)-(1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydrobenzo[h]isoquinoline;

Compound 15: (2-cyclohexylethyl)-8-{2-[(2S)-(1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydrobenzo[h]isoquinoline;

Compound 16: (2-cyclohexylethyl)-8-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline;

Compound 17: (2-cyclohexylethyl)-8-[2-(1-methylpiperidin-2-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline;

Compound 20: 2-butyl-7-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydroisoquinoline;

Compound 21: 2-butyl-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

The connection 22: 7-[(1-mutilation-4-yl)oxy]-2-propyl)-1,2,3,4-tetrahydroisoquinoline;

The connection 23: 7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-2-propyl-1,2,3,4-tetrahydroisoquinoline.

On the other hand, in the framework of the present invention under the protective group Pg to understand a group, which allows, on the one hand, to protect a reactive functional group such as hydroxy or amine during a synthesis and, on the other hand, to regenerate the whole of reaktsionnosposobnykh the th functional group at the end of the synthesis. Examples of protective groups and methods of protection and removal of protection are given in “Protective groups in Organic Synthesis, 3 Ed”, Green et Wuts (John Wiley and Sons, Inc., New York, 1999).

The second object of the invention is a method of obtaining compounds of the formula I according to the invention.

Thus, the compounds of formula I can be obtained by the method depicted in scheme 1.

Scheme 1

In accordance with the method depicted in scheme 1, compounds of formula I, in which R1, R2, l, m, n, and the cycle And such, as defined under the formula I, get nucleophilic substitution by reacting the phenol of formula II in which R2 and cycle And such, as defined under the formula I, with an amine of the formula III in which R1, l, m and n are such as defined for formula I, and Y denotes a halogen atom such as chlorine, iodine or bromine, or represents "pseudo-halogen, such as mesilate, triplet, toilet, bracelet or nosrat. Interaction can be done in a proton or an aprotic solvent such as water, methanol, acetone, butanone, ethyl acetate, toluene, N,N-dimethylformamide, acetonitrile or a mixture of these solvents at temperatures from 0 to 110°C in the presence of a base, such as, for example, sodium hydroxide or potassium hydroxide, sodium carbonate or potassium, triethylamine or diisopropylethylamine, to obtain the compounds of formula I. In the case of immiscible solvents can use the ü catalyst phase transformations, such as ammonium salt or phosphonium, preferably bromide or tetrabutylammonium chloride of tetraethylammonium in a mixture of toluene and water at a temperature of from 20 to 110°C. if necessary, the compounds of formula II and III can be pre-protect before you spend interaction methods known to the expert. Then, possibly with the compounds of formula I disable the protection in conditions known to the expert.

In the embodiment, the compounds of formula I can be obtained by the reaction of the Mitsunobu type. In accordance with this variant is injected into the interaction of the phenol of formula II in which R2 and cycle And such, as defined under the formula I, with an amine of the formula III in which R1, l, m and n are such as defined for formula I, but Y represents a hydroxy group, obtained by the methods known to the expert. Interaction can be a traditional method in the presence of Mitsunobu reagents, such as isoprostane, such as diethylazodicarboxylate, diisopropylsalicylic, di-tert-utilisationbased, 1,1'-(azodicarbon)piperidine or N,N,N',N'-tetramethyldisiloxane, and a phosphine, for example triphenylphosphine or tributylphosphine. The interaction can be performed in an aprotic solvent such as tetrahydrofuran or dioxane, or mixtures of these solvents, at temperatures from 0 to 100°C to obtain the compounds of formula I. If the reagents were preliminary step is correctly secured before the interaction, with the compounds of formula I disable the protection in conditions known to the expert.

Protected (formula VI) or unprotected (formula II) starting compound can be obtained according to scheme 2, or can be synthesized by traditional methods known to the expert, such as described in Journal of Medicinal Chemistry 40, 3997-4005 (1997) or etrahedron Assymmetry 12, 2427-2434 (2001).

Scheme 2

In accordance with the method depicted in scheme 2, compounds of formula II in which R2 is as defined for formula I, but is not a hydrogen atom, receive amino recovery by reacting a secondary amine of the formula IV in which R2 denotes H, aldehyde or ketone of the formula V, in which R3 and R4 after interaction R2 form together, such as defined by formula I, and are not hydrogen. The compounds of formula IV in which R2 denotes a hydrogen atom, can be obtained by traditional methods known to the expert, such as described in Journal of Medicinal Chemistry 40, 3997-4005 (1997). The compounds of formula II can then be obtained from compounds of formula VI, which are unsecured, under conditions known to the specialist. For example, if Pg is methyl group, protection from compounds of formula VI can be removed in the presence of acid, such as Hydrobromic acid, proton solvent such as water or acetic acid, or a mixture of these RA the creators at a temperature of from 0 to 100°C in the presence or in the absence of catalyst phase transformations, such as ammonium salt or phosphonium, to obtain a phenol of the formula II. The method is illustrated by the examples.

In a variant of the method according to scheme 3, the compounds of formula II in which R2 is as defined for formula I, but is not a hydrogen atom, can be obtained by reacting a protected compound of formula VI in which R2 denotes benzothiazolylthio group, obtained, for example, by the method described in etrahedron Assymmetry 12, 2427-2434 (2001), with an alkylation agent, such as an appropriate Grignard reagent.

Scheme 3

In accordance with this variant, the compounds of formula II in which R2 is as defined for formula I, can be obtained by nucleophilic substitution by the interaction of the compounds of formula VI, in which R2 denotes benzothiazolylthio group with a Grignard reagent of the formula VII, in which W denotes a halogen atom such as chlorine, iodine or bromine, and R5 denotes a (C1-5)alkyl, (C1-2)perhalogenated, (C1-3)halogenated, (C3-6)cycloalkyl, monocyclic heteroaryl, such as thienyl or furyl or aryl group such as phenyl or naphthyl; after interaction get compound of formula II in which R2 is as defined for formula I, and is not hydrogen. Interaction can be done in aproton the m solvent, such as simple diethyl ether, tetrahydrofuran or dioxane, or a mixture of these solvents at temperatures from -70 to 100°C. to obtain compound of formula VI. Then the compounds of formula II can be obtained from compounds of formula VI, which are unsecured in conditions known to the specialist. For example, if Pg is methyl group, protection from compounds of formula VI can be removed in the presence of acid, such as Hydrobromic acid, proton solvent such as water or acetic acid, or a mixture of these solvents, at temperatures from 0 to 100°C in the presence or in the absence of catalyst phase transformations, such as ammonium salt or phosphonium, to obtain a phenol of the formula II. The method is illustrated by the examples.

The original compound (II) and amines of formula III are commercially available or can be synthesized by the methods described above, by methods known to the expert or known from the literature.

In accordance with another aspect of the object inventions are the medicinal product containing the compound of formula I or salt of joining the latter with a pharmaceutically acceptable acid, or a hydrate or MES the compounds of formula I.

These compounds of the present invention are used in therapy, in particular, for treating disorders in which the improvement occurs when the modulating receptor sub> 3histamine, and for the treatment of pathologies in which therapeutic effect is achieved by the receptor antagonist of the histamine type H3. In particular, such diseases are obesity and diabetes.

These compounds with the properties of the antagonist and inverse agonist of the receptor N3histamine, used in the treatment of diseases of the Central nervous system.

Also, these compounds can be used in the treatment of diseases of the Central nervous system, such as insomnia, narcolepsy, Alzheimer's disease and other forms of dementia, Parkinson's disease, disorders of attention hyperkinetic children, impaired memory and learning difficulties, epilepsy, schizophrenia, moderate mental processes, leading to knowledge and action, depression and anxiety. To the States of depression and anxiety include, for example, the anxiety caused by waiting (before surgery, before dental treatment etc), anxiety caused by alcohol, drug addiction, mania, seasonal emotional disorders, migraine and nausea. They can also be used in the treatment of sexual dysfunction, dizziness and nausea in motion sickness.

The use of compounds according to the invention for obtaining a medicinal product intended for the treatment of the above pathologies, are the two which is part of the invention.

In accordance with another of its aspects the present invention relates to pharmaceutical compositions containing as active ingredient at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt or hydrate or MES specified connection, and at least one or more pharmaceutically acceptable excipients. These excipients is selected depending on the dosage form and the desired method of introduction of the conventional excipients known to the expert.

In the form of pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, local, local, intratracheal, intranasal, transdermal or rectal introduction of the active substance mentioned formula I or its salt, MES or hydrate can be entered as a single form of introduction in a mixture with conventional pharmaceutical excipients animals or humans for the prophylaxis or treatment of the above disorders or diseases.

To the relevant standard dosage forms include forms for oral administration such as tablets, soft or hard gelatin capsules,powders, granules and solutions or suspensions for oral administration, the forms for sublingual, buccal, intratracheal, intranasal, administration by inhalation, forms for topical, percutaneous, subcutaneous, intramuscular or intravenous administration, the forms for rectal administration and implants. For topical application it is possible to use the compounds according to the invention in creams, gels, ointments or lotions.

To obtain the desired prophylactic or therapeutic effect, the dose of active ingredient can vary from 0.1 μg to 50 mg per 1 kg of body weight per day. Each single dose may contain from 0.1 to 1000 mg, preferably from 0.1 to 500 mg of active ingredient in combination with pharmaceutically acceptable excipients. This single dose can be administered 1 to 5 times a day in order to enter the daily dose of from 0.5 to 5000 mg, preferably from 1 to 2500 mg.

In some cases the dose may be higher or lower. Such doses also belong to the invention. In usual practice, the dosage for each patient is determined by the physician depending on the method of administration, the weight and response of the patient.

As an example, a standard dosage form of the compounds according to the invention contains:

The connection according to the invention 50.0 mg

Mannitol 223,75 mg

Croscarmellose sodium 6.0 mg

The Kukura the hydrated starch 15,0 mg

The hypromellose of 2.25 mg

Magnesium stearate 3,0 mg

In accordance with another aspect of the present invention relates also to a method of treatment of the above pathologies, which includes the introduction to the patient an effective dose of the compounds according to the invention or one of its pharmaceutically acceptable salt or hydrate or solvate.

The following examples illustrate the methods and technologies of realization of this invention, without limiting its scope.

Example 1: Oxalate (2:1) (2-cyclohexylmethyl)-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline

1.1. 2-(cyclohexylmethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

In the solution 10,41 g (0.035 mol) of 2-(1H-1,2,3-benzotriazol-1-ylmethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline in 150 ml of tetrahydrofuran, cooled to -40°C, enter 35 ml (0,070 mol) of a solution of 2N cyclohexylidene chloride in tetrahydrofuran. Stirred for two hours at 40°C., then the mixture was incubated for one night at room temperature. Add a solution of 2N sodium hydroxide (50 ml). The aqueous phase is extracted 3 times using 20 ml simple ethyl ether and the organic phase is dried and evaporated in vacuum. Get to 8.20 g of oil which is used without further purification.

Rdt: 90%

PF = oil

1.2. The hydrobromide of 2-(cyclohexylmethyl)-1,2,3,4-t is traditioinal-7-ol

The solution to 8.20 g (to 0.032 mol) of 2-(cyclohexylmethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline in 80 ml of aqueous hydrogen bromide (48%) is heated for 6 hours to 120°C. the Mixture is cooled, concentrated to dryness and the residue is treated with 60 ml of a mixture of ethanol/simple ethyl ester. The formed solid is filtered, washed simple with ethyl ether and dried. Get to 9.70 g of the desired product in the form of a pure substance of white color.

Rdt: 94%

PF=210-214°C

1.3. Oxalate (2:1) (2-cyclohexylmethyl)-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline

In a mixture of 5.00 g (at 0.020 mol) of the compound obtained in stage 1.2, 11.2 g (0,0061 mol) of 2-(2-chloroethyl)-1-methylpyrrolidine and 0.41 g (0.002 mol) of triethylamine chloride in 125 ml of toluene is injected a mixture of 9.7 g (0,244 mol) of sodium hydroxide in 125 ml of water. The reaction mixture is heated under reflux for 8 hours. The phases are separated and the aqueous phase is extracted with twice 20 ml of toluene. The organic phase is dried, then evaporated to dryness. Get 7 g (97%) raw oil, which is purified by chromatography on a column of silica gel with a mixture of dichloromethane/methanol (98:2)was used as eluent. Target product (0,70 g; 10%) are obtained in the form of an oil with the highest Rf.

1H-NMR (CDCl3) δ (ppm):and 7.1 (1H, d), 6,7 (1H, d), and 6.5 (1H, s), 4,0 (2H, m), 3,5 (2H, s), and 3.0 (1H, m), 2,7 (2H, m), and 2.6 (2H, m), 2,4 (3H, s), 2,2 (2H, d), and 2.1 (2H, m) 2,0 (1H, m), and 1.7 (11H, m), 1,1 (3H, m), and 0.9 (2H,,m).

The above oil (0.65 g; 0.002 mol) dissolved in 10 ml of ethanol, then give 0.36 g (0,004 mol) of oxalic acid, dissolved in 10 ml of ethanol. The precipitate is filtered and washed with cold ethanol. Receive and 0.46 g of the desired product in the form of a solid white color.

Rdt: 47%

PF=78-98°C

Example 2: Oxalate (2:1) (2-cyclohexylmethyl)-7-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydroisoquinoline

In accordance with the method described above in stage 1.3, get the oil with the lowest received Rf (1,30 g, 0.002 mol), which corresponds to the structure of (2-cyclohexylmethyl)-7-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydroisoquinoline.

1H-NMR (CDCl3) δ (ppm):and 7.1 (1H, d), 6,7 (1H, d), and 6.5 (1H, s), 4,5 (1H, m), 3,5 (2H, s), 2,7 (2H, m), 2,6-2,4 (5H, m), 2,3 (3H, s), 2,2 (2H, d), and 2.0 (2H, m), and 1.7 (11H, m), 1,1 (3H, m), and 0.9 (2H, m).

The oil is dissolved in 12 ml of ethanol, then give 0.24 g (of 0.003 mol) of oxalic acid, dissolved in 12 ml of ethanol. The precipitate is filtered and washed with cold ethanol. Receive and 0.46 g of the desired product in the form of a solid white color.

Rdt: 86%

PF=110-112°C

Example 3: Oxalate (2:1) (2-cyclohexylethyl)-8-[(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline

3.1. (2-cyclohexylethyl)-8-methoxy-1,2,3,4-tetrahydrobenzo[h]quinoline

To a solution of 3 g (0.014 mol) of 8-methoxy-1,2,3,4-tetrahydrobenzo[h]Hino the ins and 1.6 g (0.014 mol) of cyclohexanecarboxaldehyde in 70 ml of methanol is injected 0.32 g (0,0003 mol) and 10%palladium on coal. The solution hydronaut in 24 hours in hydrogenating the tool Paar under pressure of 45 Psi. The catalyst was eliminated by filtration and the filtered solution is evaporated to dryness. Get 4 g of the target product in the form of oil.

Rdt: 93%

PF=oil

3.2. (2-cyclohexylmethyl)-1,2,3,4-

tetrahydrobenzo[h]isoquinoline-7-ol hydrobromide

A solution of 2 g (0,006 mol) (2-cyclohexylethyl)-8-methoxy-1,2,3,4-tetrahydrobenzo[h]quinoline in 30 ml of aqueous hydrogen bromide (48%) is heated for 6 hours to 120°C. the Mixture is cooled, concentrated to dryness and the residue treated with 20 ml of a mixture of ethanol/simple ethyl ester. The formed solid is filtered, washed simple with ethyl ether and dried. Obtain 2.3 g of the desired product in the form of a pure solid white color.

Rdt: 96%

PF=270-276°C

3.3. Oxalate (2:1) (2-cyclohexylethyl)-8-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline

In a mixture of 2.00 g (0,005 mol) of the compound obtained in stage 3.2, 2.4 g (0.014 mol) of 2-(2-chloroethyl)-1-methylpyrrolidine and 0.11 g (0,0006 mol) of triethylamine chloride in 75 ml of toluene is introduced into a mixture of 2.5 g (0,064 mol) of sodium hydroxide in 75 ml of water. The reaction mixture is heated under reflux for eight hours. The phases are separated and the aqueous phase is extracted with 2 times 20 ml of toluene. The organic phase is dried, then evaporated to dryness. Get 3 g (>100%) crude wt is a, which is purified by chromatography on a column of silica gel using mixtures of dichloromethane/methanol (98:2)was used as eluent. Target product (0,70 g; 10%) are obtained in the form of an oil with the highest Rf.

1H-NMR (CDCl3) δ (ppm): 7,7 (1H, d), and 7.5 (1H, d), a 7.1 to 7.0 (3H, m), 4.2V (2H, m), 4,0 (2H, s), and 3.0 (1H, m), 2,9 (2H, m), 2,7 (2H, m), 2,4 (2H, d), and 2.3 (3H, s), 2,2-2,0 (3H, m), and 1.7 (11H, m), 1,1 (3H, m)at 0.9 (2H, m).

The above oil (0.5 g, 0.001 mol) is dissolved in 10 ml of ethanol, then give 0.24 g (of 0.003 mol) of oxalic acid, dissolved in 10 ml of ethanol. The precipitate is filtered and washed with cold ethyl ether, obtain 0.50 g of the desired product in the form of a solid white color.

Rdt: 70%

PF=127-135°C

Example 4: Oxalate (2:1) (2-cyclohexylethyl)-8-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline

In accordance with the method described above at the stage 3.3, get the oil with the lowest received Rf of 0.67 g, 0.002 mol), which corresponds to the structure of (2-cyclohexylmethyl)-7-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydroisoquinoline.

1H-NMR (CDCl3) δ (ppm):), and 7.8 (1H, d), and 7.6 (1H, d), a 7.2 to 7.0 (3H, m), 4,7 (1H, m), 4,0 (2H, s), and 3.0 (2H, m), 2,9 (2H, m), 2,7 (2H, m), 2,4 (2H, d), and 2.3 (3H, s), 2.3 percent and 1.7 (14H, m), 1,1 (3H, m), and 0.9 (2H, m).

The oil is dissolved in 10 ml of ethanol, then enter 0,37 g (0,004 mol) of oxalic acid, dissolved in 10 ml of ethanol. The precipitate is filtered and washed with cold ethyl alcohol and sex is with 0.25 g of the desired product in the form of a solid white color.

Rdt: 31%

PF=77-101°C

Example 5: Hydrochloride (2:1) (2-cyclohexylmethyl)-7-{2-[(2S)-(1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline

In a mixture of 7.3 g (0,030 mol) of 2-(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinoline-7-ol obtained above in stage 1.2, 3.5 g (or 0.027 mol) of (S)-2-(2-hydroxyethyl)-1-methylpyrrolidine and 9.2 g (being 0.036 mol) of triphenylphosphine in 150 ml of tetrahydrofuran, cooled to -5°C, injected 6.6 g (to 0.032 mol) of diisopropylcarbodiimide. Stirred over night at room temperature. The solution is evaporated to dryness and receive crude oil, which is purified by chromatography on a column of silica gel using mixtures of dichloromethane/methanol (95:5), is used as eluent. Target product (1.4 g; 15%) are obtained in the form of oil.

1H-NMR (CDCl3) δ (ppm):and 7.1 (1H, d), 6,7 (1H, d), and 6.5 (1H, s), 4,0 (2H, m), 3,5 (2H, s), and 3.0 (1H, m), 2,7 (2H, m), and 2.6 (2H, m), 2,4 (3H, s), 2,2 (2H, d), and 2.1 (2H, m) 2,0 (1H, m), and 1.7 (11H, m), 1,1 (3H, m), and 0.9 (2H,, m).

The oil is dissolved in 25 ml of isopropanol, then isopropanol saturated with HCl. The precipitate is filtered and washed with 1 ml of cold isopropanol. Receive 1 g of the target product in a solid white color.

Rdt: 59%

PF=238-241°C

Example 6: Hydrochloride (2:1) (2-cyclohexylethyl)-8-[(2S)-(1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydrobenzo[h]isoquinoline

In a mixture of 2.2 g (to 0.007 mol) of 2-(cyclohexyl the Teal)-1,2,3,4-tetrahydrobenzo[h]isoquinoline-7-ol, obtained above in stage 3.2, 0.95 g (to 0.007 mol) of (S)-2-(2-hydroxyethyl)-1-methylpyrrolidine and 2.14 g (0,008 mol) of triphenylphosphine in 150 ml of tetrahydrofuran, cooled to -5°C, injected 1.88 g (0,008 mol) of diisopropylcarbodiimide. Stirred over night at room temperature. The solution is evaporated to dryness and receive crude oil, which is purified by chromatography on a column of silica gel using mixtures of dichloromethane/methanol (95:5), is used as eluent. Target product (1.1 g; 36%) are obtained in the form of oil.

1H-NMR (CDCl3) δ (ppm):), and 7.7 (1H, d), and 7.5 (1H, d), a 7.1 to 7.0 (3H, m), 4.2V (2H, m), 4,0 (2H, s), and 3.0 (1H, m), 2,9 (2H, m), 2,7 (2H, m), 2,4 (2H, d), and 2.3 (3H, s), 2,2-2,0 (3H, m), and 1.7 (11H, m), 1,1 (3H, m), and 0.9 (2H, m).

The oil is dissolved in 15 ml of isopropanol, then isopropanol saturated with HCl. The precipitate is filtered and washed with 1 ml of cold isopropanol. Obtain 0.8 g of the desired product in the form of a solid white color.

Rdt: 62%

PF=260°C

The following table illustrates the chemical structures and physical properties of a few compounds according to the invention. Elemental microanalysis and NMR spectra, infrared and mass spectrometry confirmed the structure of the compounds obtained.

In the table “P.F.” compounds of formula I corresponds to the melting point, and “Config” indicates the stereochemical configuration, namely (R), (S) - or racemic mixture (R,S) carbon atoms, seat the frame with an asterisk (*).

Compounds according to the invention corresponding to formula I, it became the subject of pharmacological trials which showed that the compounds are of interest as active compounds in therapy.

More specifically, the compounds according to the invention are antagonists of the histamine receptor type H3. Receptor type H3well-known specialist, and the interest that they represent in the treatments described in the literature ("Histamine H3receptor antagonists" Exp. Opinion Ther. Patents (2000) 10 (7): 1045-1055). Thus, the compounds according to the invention of formula I were tested for affinity in vitro to natural histamine receptor type H3in the membrane preparation of the brain of adult rats through a specific communication [3H]-N-α-methylhistamine with this receptor methods described Korte A, et al. in Biochem. Biophys. Res. Commun. 168, 979-986(1990) and West, R.E.Jr et al. in Mol. Pharmacol. 38, 610-613(1990).

Kicompounds according to the invention in relation to the receptor N3is in the range from 0.1 nm to 50 μm, and more specifically (2-cyclohexylethyl)-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline (see compound 5 in the table) has the Ki0.1 nm.

Compounds according to the invention of formula I were tested on education camp at the human histamine receptor type H3displaced cells SNO is ay inhibiting agonism, the result of the unique relationship of R-α-methylhistamine with this receptor methods described Lovenberg, .W. et al., in J.Pharmacol. Exp. Ther. 293, 771-778 (2000).

CI50compounds according to the invention in relation to the receptor N3is from 0.1 nm to 5.0 μm.

As an example, the compound 5 in the table, has a CI50<10 nm, and the dimension of education camp was conducted with the help of the device EIA (Amersham) on human histamine receptor type H3displaced cells SNO by inhibiting agonism, the result of the unique relationship of R-α-methylhistamine with this receptor.

Compounds according to the invention have selective activity against histamine receptor type H3. Indeed, the compounds have a Ki above 7.0 µm in the test for affinity in vitro to natural histamine receptor type H3in the membrane preparation of the brain of adult rats through a specific communication [3H]-N-pyrilamine with this receptor by the method described by Liu Y.Q. et al. in J. Pharmacol. Exp. Ther 268, 959 (1994).

1. The compounds of formula I

in which

denotes unsaturated carbocycle with double bonds, which are selected from phenyl or naphthyl;
l can take values from 1 to 3;
m can take values 0, 2, or 3;
n can take a value of 0 or 2;
R1 denotes a hydrogen atom,
(C 1-3)alkyl group;
R2 denotes
(C1-6)alkyl group which may be substituted by the Deputy, is selected from C6-cycloalkyl, monocyclic heteroaryl selected from thiophene, aryl group selected from phenyl,
in the form of a base or salt of joining with acid.

2. The compounds of formula I according to claim 1, having the following names:
1: 7-{2-[1-methylpiperidin-2-yl]ethoxy}-2-propyl-1,2,3,4-tetrahydroisoquinoline;
2: 2-isobutyl-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;
3: 2-(3-methylbutyl)-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;
4: 7-[(1-mutilation-4-yl)oxy]-2(3-methylbutyl)-1,2,3,4-tetrahydroisoquinoline;
5: (2-cyclohexylmethyl)-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;
6: (2-cyclohexylmethyl)-7-{2-[(2R)-1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline;
7: (2-cyclohexylmethyl)-7-{2-[(2S)-1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline;
8: (2-cyclohexylmethyl)-7-[(1-mutilation-4-yl])oxy]-1,2,3,4-tetrahydroisoquinoline;
9: (2-cyclohexylmethyl)-7-[2(1-methylpiperidin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;
10: 2-benzyl-7-[2(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;
11: 2-benzyl-7-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydroisoquinoline;
12: 7-[(1-mutilation-4-yl)oxy]-2-(2-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline;
13: (2-cyclohexylethyl)-8-[2(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline;
14: (2-cyclohexylethyl)-8-{2-[(2R)-1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydrobenzo[h]isoquinoline;
15: (2-cyclohexylethyl)-8-{2-[(2S)-1-methylpyrrolidine-2-yl]ethoxy}-1,2,3,4-tetrahydrobenzo[h]isoquinoline;
16: (2-cyclohexylethyl)-8-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline;
17: (2-cyclohexylethyl)-8-[2-(1-methylpiperidin-2-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h]isoquinoline;
20: 2-butyl-7-[(1-mutilation-4-yl)oxy]-1,2,3,4-tetrahydroisoquinoline;
21: 2-butyl-7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;
22: 7-[(1-mutilation-4-yl)oxy]-2-propyl)-1,2,3,4-tetrahydroisoquinoline;
23: 7-[2-(1-methylpyrrolidine-2-yl)ethoxy]-2-propyl-1,2,3,4-tetrahydroisoquinoline;
and their pharmaceutically acceptable salts.

3. Pharmaceutical composition having the properties of the receptor antagonist of the histamine type H3containing the compound of the formula I according to any one of claims 1, 2, or its salt in an effective amount and at least one pharmaceutical excipient.

4. The use of the compounds of formula I according to any one of claims 1, 2, or its salt, to obtain a medicinal product intended for treating obesity and/or diabetes.

5. The use of the compounds of formula I according to any one of claims 1, 2, or its salt, to obtain a medicinal product intended for the treatment of a disease selected from disorders of the Central nervous system, disorders of the on, narcolepsy, Alzheimer's disease and other types of dementia, Parkinson's disease, disorders of attention hyperkinetic children, impaired memory and learning difficulties, epilepsy, schizophrenia, moderate mental processes leading to knowledge and action, depression and anxiety, state anxiety caused by the expectation or alcohol, drug addiction, mania, seasonal emotional disorders, migraines and nausea.

6. The use of compounds of formula II

in which Pg denotes a hydrogen atom or a protective group, and R2 and As such, as defined in any one of claims 1, 2, to obtain the compounds of formula I according to any one of claims 1, 2.

7. Method of producing compounds of the formula I, in which R1, R2, l, m, n, and the cycle And such, as defined under the formula I according to any one of claims 1, 2, by carrying out the following reactions:

which is nucleophilic substitution by reacting the phenol of formula II in which R2 and cycle And such, as defined under the formula I, with an amine of the formula III in which R1, l, m and n are such as defined for formula I, and Y denotes a halogen atom, or denotes pseudohalogen, such as mesilate, triplet, toilet, bracelet or nosrat, or denotes a hydroxy group.

8. The method of receiving according to claim 7, in which the compound of formula II get amino recovery is here the interaction of the secondary amine of the formula IV, in which R2 denotes H,

with aldehyde or ketone of the formula V (R3R4C(0)), where R3 and R4 form together in the reaction R2, such as defined by formula I and paulauskis hydrogen, according to the formula VI

possibly with a subsequent removal of the protection.

9. The method of receiving according to claim 7, in which the compound of formula II get nucleophilic substitution by reacting the compounds of formula VIa, in which R2 denotes benzothiazolylthio group,

with a Grignard reagent of formula VII R5MgW, where W denotes a halogen atom selected from chlorine, iodine and bromine, and R5 denotes a6-cycloalkyl, monocyclic heteroaryl selected from thiophene, or aryl group selected from phenyl; after interaction get compound of formula VIb in which R2 denotes CH2R5

possibly with a subsequent removal of the protection.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, in which X is or ; Y is H; Z is -C(O)-; R1 and R3 each independently denotes H or (C1-C4) alkyl; R2 and R4 each independently denotes , , or ; R5 denotes H or (C1-C6) alkyl; R8 and R9 each independently denote (C1-C6) alkyl; and Q is H.

EFFECT: possibility of use in stimulating the growth hormone in a subject based on the said compounds.

49 cl, 2 tbl, 57 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds described by formula in which radical and symbol values are specified in the patent claim, and their pharmaceutically acceptable salts. These compounds inhibit tompomyosine-related kinases (Trk), and can find application in treating a malignant growth, such as breast cancer, rectal cancer and prostate cancer. Also, the invention relates to a method for producing these compounds, a based pharmaceutical composition and to methods of application thereof.

EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

18 cl, 134 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), where R2 denotes H, [(C1-C6) alkylene]0-1-R'; R3 denotes H; R4 denotes H, halogen or (C1-C6) alkyl; R5 denotes H or halogen; R6 denotes H, (C1-C8) alkyl, R', (C1-C6) alkylene-R'; R7 and R8 independently denote H, halogen, (C1-C6) alkyl, O-(C1-C6) alkyl, R'; R9 denotes (C1-C6)alkyl; n equals 0 or 1; L denotes O or O-(C1-C6)alkylene; where R' denotes (C3-C8) cycloalkyl; (C5-C10)heterocyclyl, which denotes an aromatic or saturated mono- or bicyclic ring system which, besides a carbon atom, includes one or more heteroatoms such as nitrogen, oxygen and sulphur atoms; or (C6-C10) aryl; where in the heterocyclyl is unsubstituted or substituted with (C1-C6)alkyl, and the aryl is unsubstituted or substituted with a halogen, (C1-C4)alkyl, -O-(C1-C4)alkyl, SO2- (C1-C4) alkyl or N[(C1-C4) alkyl]2; and where in groups R4, R6 and R7 the alkyl can be halogenised in one or more positions; or pharmaceutically acceptable salts and/or stereo isomer forms thereof. The invention also relates to use of formula (I) compounds, as well as a medicinal agent.

EFFECT: obtaining novel biologically active compounds having Rho-kinase inhibiting activity.

21 cl, 320 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula 1, its pharmaceutically acceptable salts and stereoisomers: $ (1), where: R1 means H, amidino, C1-C4-alkyl amidino, C1-C4alkanoylamidino, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, 6-members heterocycle with O atom, 5-members heterocycle with two N atoms, 6-members heteroaryl with one or two N atoms, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7); and, R6, R7 means H, C1-C6-alkyl, C3-C7-cycloalkyl; alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted or substituted; R2 means C6-C10-aryl which is unsubstituted or mono- or disubstituted; R3 means H, CN, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6-alkenyl, monocyclic 5-members heterocycle with N and O, monocyclic 5-members heteroaryl with two heteroatoms, one of which is N, and the other is O or S, C(O)-R8 or -C(S)-R8; and R8 means OH, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10); R9, R10 mean N, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyloxy, phenyl or 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N; R9, R10 together with N whereto attached can form a single 4-6-members ring which can include in addition O or S; and alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are unsubstituted or substituted. R4 means C3-C8-cycloalkyl, C6-C10-aryl, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N, 6-members heterocycle with O, and C6-C10-aryl or heteroaryl are unsubstituted or mono- or polysubstituted. R5 means N, C1-C6-alkyl, -C(O)-R11, C1-C6-alkylsulphonyl, C6-C10-arylsulphonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl means 5-members heteroaryl with O or with N or with S which can contain in addition N. p is equal to 1 or 2; R11 means C1-C10-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, NH2, C1-C4alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-members heteroaryl with N or with O or with 8 which can contain in addition N, 6-members heterocycle with N and O, 5- or 6-members heterocycle with O, and alkyl is unsubstituted or substituted with one substitute. Aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle are unsubstituted or mono- or disubstituted.

EFFECT: compounds are melanocortin receptor agonists so presented to be used in a pharmaceutical composition for treatment and prevention of obesity, diabetes, inflammation, erectile dysfunction.

19 cl, 18 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of compounds, characterised by formulae (I) and (IB), or pharmaceutically acceptable salts thereof, isomers or hydrates to prepare a medicinal agent for treating or preventing diseases or conditions mediated by the sigma-receptor, selected from psychosis, neuropathic pain or inflammatory pain and movement disorder, such as dystonia or tardive dyskinesia, motor defects, including allodynia/or hyperalgesia. Radicals and symbols in compounds of formulae (I) and (IB) are described in claims 1 and 2. The invention also relates to novel compounds of formulae (I') and (IB'), in which radicals and symbols are described in claims 4 and 5, having pharmacological activity on the sigma-receptor, methods of producing such compounds, a pharmaceutical composition containing said compounds and use of said compounds in preparing a medicinal agent for treating and/or preventing diseases or conditions whose development involves the sigma-receptor. (I), (IB) (I') and (IB').

EFFECT: high effectiveness of the inhibitors.

22 cl, 1 tbl, 3 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds which are methyl-3-azabicyclo[3.3.0]octane-7-carboxylate, N-methyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, N-propyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, or pharmaceutically acceptable salts thereof. The invention also relates to compounds selected from a group, a pharmaceutical composition, methods of treating or preventing central nervous system disorders, as well as use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds having activity on neural nicotinic acetylcholine receptor.

11 cl, 14 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, where R1 -OH, R2- CONAA', SO2NAA', SO2NA-benzyl, SO2NHAr, SO2NAHet, SO2NHA or S(O)mHet, R3, R5, R6 - H, R4 - H, Hal or A, Y - OH, A, A' denotes a straight or branched C1-C10 alkyl, in which one CH2 group can be substituted with NR8, where R8 denotes a straight or branched C1-C6 alkyl or cycloalkyl, Ar denotes phenyl, Het denotes a saturated C5-C6-heterocyclic ring containing 1-2 nitrogen atoms, which can be substituted with A, m equals 1 or 2, and pharmaceutically suitable salts or tautomers thereof. The invention also relates to a method of producing said compounds and pharmaceutically suitable salts or tautomers thereof. The invention also relates to use of said compounds, salts or tautomers to prepare a medicinal agent for treating and/or preventing diseases affected by HSPS90 inhibition, as well as a medicinal agent based on said active ingredients, having HSP90 inhibiting activity. The invention also relates to an intermediate compound of formula I-1, where Z denotes A, Y - OH, R1 - OCH3, R2 - SO2Het, SO2NHAr or SO2NAA', R3 - H, R4 - Hal or A, R5, R6 - H, Ar - phenyl, Het - saturated C5-C6-heterocyclic ring, containing 1-2 nitrogen atoms which can be substituted with A, A, A' - straight or branched C1-C10 alkyl.

EFFECT: high efficiency of the composition.

6 cl, 1 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or pharmaceutically acceptable salts thereof, where Q is CH or N; R2 is C1-C4 alkyl or C3-C4-cycloalkyl; Y is R5-O; where R5 is propynyl; X is selected from a group consisting of aryl, heteroaryl, C1-C5-alkyloxy, heterocycloalkyl, arylamino, heteroarylamino, heteroaryl-C1-C4-alkylamino, aryloxy, aryl-C1-C2-alkyloxy or C3-C6-cycloalkyl-C1-C4-alkyloxy, each of which is optionally substituted with 1-3 times; the optional substitute(s) for X is(are) independently selected from a group comprising halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkyloxy-C1-C4-alkoxy, -SMe, SO2-C1-C2-alkyl, -NMe2, - C(O)O-C1-C5-alkyl, -SCF3, -SO2-NH2, -SO2-C2-alkyl-OH, -CONH2, -COMe, - CONH-C1-C4-alkyl, -CONMe2, -NHCOMe, -CH2COOEt, -OCH2COOEt, -CH2- cyclopropyl, and each R3 and R4 is H; where aryl denotes phenyl or naphthyl; heteroaryl denotes monocyclic or bicyclic hydrocarbon containing 5-10 ring atoms, one or more of which are heteroatoms selected from O, N or S; heterocyclyl denotes piperidinyl or benzodioxolyl; or a compound or pharmaceutically acceptable salt thereof, selected from a group comprising (4-dimethylaminophenyl)-[4-(4-cyclopropylphenyl)-6-propargyloxyquinazolin-2-yl]methanone, (3-sulphamoylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, [3-(2-hydroxyethanesulphonyl)phenyl]amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methylsulphanylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methanesulphonylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, and (5-ethanesulphonyl-2-hydroxyphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4- dihydroquinazoline -2-carboxylic acid. The invention also relates to a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel benzoquinazoline derivatives, which are useful in treating bone disorders, are obtained.

6 cl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds described by formula in which radical and symbol values are specified in the patent claim, and their pharmaceutically acceptable salts. These compounds inhibit tompomyosine-related kinases (Trk), and can find application in treating a malignant growth, such as breast cancer, rectal cancer and prostate cancer. Also, the invention relates to a method for producing these compounds, a based pharmaceutical composition and to methods of application thereof.

EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

18 cl, 134 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclylsubstituted imidazole derivatives of general formula or to its pharmaceutically acceptable salts wherein R1 stands for a group of formula where * stands for a position whereon a carbonyl group is bound, R4 stands for phenyl or pyridyl, and phenyl or pyridyl can be substituted by one substitute where the substitute is chosen from a group including haloid, nitrogroup, cyanogroup, trifluoromethyl, (C1-C6)alkyl and (C1-C6)alkoxygroup, R6 and R7 stands for hydrogen, R2 stands for (C1-C6)alkyl, and alkyl can be substituted by a substitute where the substitute is chosen from a group including (C3-C6)cycloalkyl and (C6)aryl where aryl can be substituted by a trifluoromethyl substitute, R3 stands for phenyl, and phenyl can be substituted by substitutes in number 1 to 2 independently chosen from a group including haloid, trifluoromethyl, trifluoromethoxygroup, difluoromethoxygroup, trifluoromethylthiogroup and (C1-C6)alkyl. Also, the invention refers to methods for producing compounds of formula I, to a drug prepared of the compound of formula I, to applying the compound of formula I for preparing the drug and to a method of controlling cytomegalovirus infection.

EFFECT: production of new imidazole derivatives exhibiting antiviral activity, particularly in relation to cytomegaloviruses.

10 cl, 4 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are new compounds of formula with their radical values specified in the patent claim, as well as their pharmaceutically acceptable salts exhibiting VEGFR-2 receptor KDR-kinase inhibitor activity, and drugs based on such compounds. Described is an intermediate product for preparing the compound of formula (I), and the use of this intermediate product.

EFFECT: development of an effective method for preparing the compound.

41 cl, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to hydrosulphate salt of compound 1 its solvates, crystalline forms and amorphous forms, as well as to method of obtaining them. In addition, invention relates to application of claimed salt in manufacturing of medication for treatment of MEK-mediated disease states and to methods of said state treatment.

EFFECT: elaboration of efficient method of obtaining hydrosulphate salt of compound.

16 cl, 3 ex, 3 tbl, 3 dwg

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