Derivatives of quinazoline

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinazoline of the general formula (I): , wherein R1 represents -O-R4 or -N(R5)(R6); R2 represents alkyl; R3 represents hydrogen atom; R4 represents hydrogen atom, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, pyridinylalkyl substituted with cyano-group or halogen atom, cycloalkylalkyl; R5 and R6 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, arylcarbonyl, alkoxyalkyl, hydroxyalkyl, pyridinyl, furanylcarbonyl, or R5 and R6 in common with nitrogen atom (N) to which they are added form a 5-10-membered heterocyclic ring that comprises optionally the second heteroatom chosen from nitrogen or oxygen atoms and wherein heterocyclic ring is substituted optionally with one or some substitutes chosen independently from alkyl or alkoxy-group; A represents 5-7-membered heterocyclic ring comprising nitrogen atom added to quinazoline ring, and optionally the second heteroatom that is chosen from oxygen, sulfur or nitrogen atoms and wherein ring A is substituted optionally with one or some substitutes chosen independently from alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, and their pharmaceutically acceptable salts and esters. Also, invention relates to a method for synthesis of compounds of the formula (I) and to pharmaceutical composition possessing antagonistic activity with respect to neuropeptide Y. Invention provides synthesis of novel biologically active compounds and pharmaceutical compositions based on thereof possessing antagonistic activity with respect to neuropeptide Y.

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

17 cl, 34 ex

 

The present invention relates to new derivatives of hintline that can be used as ligands, receptors, neuropeptide Y, in particular as antagonists of neuropeptide Y (NPY).

The invention relates to compounds of formula I

and their pharmaceutically acceptable salts and esters, where

R1represents-O-R4or-N(R5)(R6);

R2represents an alkyl or amino;

R3represents hydrogen, alkyl or halogen;

R4represents hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, geterotsiklicheskikh, cycloalkenyl, NH2-SO2-, amino-SO2- or alkyl-SO2-;

R5and R6independently selected from hydrogen, alkyl, cycloalkyl,

cycloalkenyl, alkylcarboxylic, cycloalkylcarbonyl, aryl, aralkyl, arylcarbamoyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, geterotsiklicheskikh, alkyl-SO2-, aryl-SO2-, heterocyclyl-SO2- or amino-SO2-, or R5and R6together with the N atom to which they are attached, form a 5-to 10-membered heterocyclic ring, which optionally includes a second heteroatom selected from nitrogen or oxygen, and where the heterocyclic ring is optionally substituted one or ascoltami substituents, independently selected from alkyl or alkoxygroup and

A is a 5-7-membered saturated heterocyclic ring including the nitrogen atom attached to hinazolinam ring, and optionally a second heteroatom selected from oxygen, sulfur or nitrogen, where the ring And optionally substituted by one or more substituents, independently selected from halogen, alkyl, alkoxy, haloalkoxy, cycloalkylation, hydroxy, amino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, haloalkoxy and cycloalkylcarbonyl.

The compounds of formula I and their pharmaceutically acceptable salts are new and possess valuable pharmaceutical properties. They are ligands of neuropeptides, such as receptor antagonists of the neuropeptides, and, in particular, these compounds are selective antagonists of the receptor Y5 neuropeptides Y.

Neuropeptide Y, consisting of 36 amino acid residues, is widely distributed in the Central and peripheral nervous system. This peptide, depending on the type of receptor to which it binds, is a mediator of various physiological effects. Experiments on animals have shown that neuropeptide Y is a potent stimulator of food intake, it was also demonstrated that the activation of the Y5 receptor for neuropeptide Y leads to GI is refugee and reduced thermogenesis. Thus, compounds that are antagonists of receptors for neuropeptide Y subtype Y5, can be used to treat eating disorders such as obesity and hyperphagia.

A modern approach to the treatment of these diseases is the medication causing weight loss or prevent its collection. This is achieved by control of the appetite, which is controlled by hypothalamus, the area of the brain that controls food intake. It has been shown that some species of animals neuropeptide Y (NPY) is one of the strongest Central mediators that control food intake. The increase of the level of NPY has led to increased food consumption. Were identified by different receptors, neuropeptide Y (NPY), play an important role in the control of appetite and weight gain. Interaction with these receptors can lead to decreased appetite and subsequent weight loss. Reduction and long-term weight stabilization may play a decisive role in reducing the associated excessive weight risk factors, such as arthritis, diseases of cardiovascular system, diabetes and renal failure.

Therefore, the compounds of formula I can be used for the prevention and treatment of arthritis, diseases of the cardiovascular system, kidney failure and, in particular, for the treatment and PR is the prevention of eating disorders and obesity.

Objects of the present invention are the compounds of formula I and their aforementioned salts and esters themselves, and their use as therapeutically active substances, the method of obtaining the above-mentioned compounds, intermediate compounds, pharmaceutical compositions, drugs containing these compounds, their pharmaceutically active salts and esters, the said compounds, their salts and esters for the prevention and/or treatment of arthritis, diseases of cardiovascular system, diabetes, renal failure and particularly eating disorders, such as hyperphagia and especially obesity, as well as the use of these compounds, their salts and esters for the production of pharmaceuticals for the treatment or prevention of arthritis, diseases of cardiovascular system, diabetes, renal failure and particularly eating disorders, such as hyperphagia and obesity.

In the present description, the term "alkyl", alone or in combination, signifies an alkyl group with straight chain or branched chain with 1 to 8 carbon atoms, preferably an alkyl group with straight or branched chain with 1-6 carbon atoms and particularly preferably an alkyl group with straight or branched chain with 1 to 4 carbon atoms. Examples of C1-C8alkyl groups with direct and R is Svetlanas chain is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric of Penteli, isomeric sexily, isomeric Gately and the isomeric octile, preferably methyl and ethyl and most preferably methyl.

The term "cycloalkyl", separately or in combination, refers to cycloalkyl ring of 3-8 carbon atoms and preferably cycloalkyl ring with 3-6 carbon atoms. Examples3-C8cycloalkyl are cyclopropyl, methylcyclopropyl, dimethylcyclopropene, cyclobutyl, methylcyclobutane, cyclopentyl, methylcyclopentene, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.

The term "alkoxy", alone or in combination, signifies a group of the formula alkyl-O-, where the term "alkyl" has the previously specified value, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, preferably methoxy, ethoxy and most preferably methoxy.

The term "aryloxy", separately or in combination, signifies a group of the formula aryl-O-, where the term "aryl" has the previously mentioned meaning, such as phenyloxy.

The term "aryl", alone or in combination, signifies a phenyl or naftalina group, preferably the phenyl group, which optionally has one or more Deputy is th, each independently selected from halogen, trifloromethyl, amino, alkyl, alkoxy, alkylsulphonyl, cyano, carbamoyl, alkoxycarbonyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, hydroxy, nitro, etc. such as phenyl, chlorophenyl, triptoreline, chlorophenyl, AMINOPHENYL, methylcarbonate, methoxyphenyl, methylenedioxyphenyl, 1-naphthyl and 2-naphthyl. Preferred is phenyl, 3-chlorophenyl, 3-triptoreline, 3-AMINOPHENYL, 4-methylcarbonate, 4-methoxyphenyl, and especially phenyl.

The term "aralkyl", separately or in combination, refers to a certain higher alkyl or cycloalkyl group in which one or more, preferably one hydrogen atom is substituted by an aryl group, as defined above. Preferred are benzyl, benzyl, substituted hydroxy, alkoxy or halogen, preferably fluorine. Especially preferred is benzyl.

The term "heterocyclyl", separately or in combination, denotes a saturated, partially unsaturated or aromatic 4-10-membered heterocycle containing one or more, preferably one or two heteroatoms selected from nitrogen, oxygen or sulfur, where the oxygen and especially nitrogen are preferred. If desired, the heterocycle may be substituted by one or more ug is arodnym atoms by halogen, the alkyl, alkoxy, oxo, cyano, haloalkyl, preferably trifluoromethyl and heterocyclyl, preferably by morpholinium and pyrrolidinium, and/or on a secondary nitrogen atom (i.e.- NH-) alkyl, cycloalkyl, alcoxycarbenium, alkanoyl, phenyl or phenylalkyl, or on a tertiary nitrogen atom (i.e. =N-) oxydipropyl, where halogen, alkyl, cycloalkyl and alkoxy are preferred. The term "heterocyclyl" also includes heteroaryl. Examples of heterocyclic groups are pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 3,4-dihydro-1H-ethenolysis, azepane, tetrahydrofuranyl and thiophenyl, and each of these rings may contain one or more, preferably one or two substituent independently selected from alkyl, alkoxy, halogen, trifloromethyl, cyano, morpholinyl and pyrrolidinyl. Preferable examples of the heterocycle is pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiophenyl, tetrahydrofuranyl and furyl, each of these rings may contain one or more, preferably one or two substituent selected from alkyl, alkoxy, halogen, trifloromethyl and cyano. Particularly preferable examples of the heterocycle are pyrrolidinyl, pyridinyl or furyl, each of these rings may be optionally substituted with halogen or cyano, before occhialino fluorine, chlorine or cyano.

The term "heteroaryl", separately or in combination, refers to an aromatic 5-to 10-membered heterocycle that contains one or more, preferably one or two heteroatoms selected from nitrogen, oxygen or sulfur, where the nitrogen or oxygen are preferred. If desired, the heterocycle may be substituted by one or more carbon atoms by halogen, alkyl, alkoxy, cyano, haloalkyl, heterocyclyl, preferably trifluoromethyl. Preferably heteroaryl cycles are pyridinyl or thiophenyl, optionally substituted by one or more, preferably one or two, substituents, independently selected from halogen, alkyl, alkoxy, cyano and haloalkyl, preferably trifluoromethyl.

The term "amino", alone or in combination, signifies a primary, secondary or tertiary amino group connected through the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl Deputy, and the tertiary amino group carrying two identical or different alkyl or cycloalkyl Deputy or two nitrogen substituent together form a ring, such as, for example, -NH2methylamino, ethylamino, dimethylamino, diethylamino, methylethylamine, pyrrolidinyl-1-yl or piperidino etc., preferably amino, dimethylamino, diethylamino and OS is especially primary amino group.

The term "halogen" denotes fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine.

The term "carbonyl", alone or in combination, refers to a group-C(O)-.

The term "hydroxyalkyl", separately or in combination, refers to alilou group that is appropriate under the definition given above, in which one or more, preferably one hydrogen atom substituted by a hydroxy-group.

The term "cyano", separately or in combination, refers to the group-CN.

The term "heterocyclic", separately or in combination, refers to a group heterocyclyl-O-, where the term heterocyclyl fits the definition given above.

The term "acetylamino", separately or in combination, signifies a group-NH-CO-CH3.

The term "pharmaceutically acceptable salt" refers to salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Such salts are obtained from inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, peruvemba acid, oxalic acid, maleic acid, malonic acid, succinic sour is a, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, N-acetylcysteine, etc. in Addition, these salts can be obtained by adding inorganic bases or organic bases, with the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, primenenie resin, etc. Compound of formula I may also be present in form zwitterions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are hydrochloride.

The compounds of formula I may also be solvated, for example gidratirovana. MES can be obtained in the production process or can be obtained, for example, the hygroscopic properties of the original waterless with the organisations of the formula I (hydration). The term pharmaceutically acceptable salts also include physiologically acceptable solvate.

"Pharmaceutically acceptable esters" means that compounds of General formula (I) can be derivationally functional groups with obtaining derivatives, which are able to turn back into the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ether derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. In addition, any physiologically acceptable equivalents of the compounds of General formula (I), such metabolically labile esters, which can be converted into the parent compound of General formula (I) in vivo, are included in the scope of the present invention.

The term "lipase inhibitor" refers to compounds that can inhibit the action of lipases, such as gastric and pancreatic lipases. For example, orlistat and lipstatin, as described in US 4598089, are strong inhibitors of lipases. Lipstatin is a natural product of microbial origin, and orlistat is the result of hydrogenation of lipstatin. Another inhibitor of lipases includes a class of compounds commonly referred to as anglicani. Anglicani are analogues of orlistat (Mutoh and others, 1994). The term "lipase inhibitor" relative to the tsya also to polymeric binding of lipase inhibitors, for example, described in WO 99/34786 (Geltex Pharmaceuticals Inc). These polymers are characterized by the fact that they have been replaced by one or more groups which inhibit the lipase. The term "lipase inhibitor" also includes pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" preferably refers to orlistat.

Orlistat is a known compound useful for the control or prevention of obesity and hyperlipidemia. Cm. US 4598089 from 01.07.1986, which also discloses methods for producing orlistat and US 6004996, which opens the corresponding pharmaceutical compositions. Further suitable pharmaceutical compositions are described, for example, in WO 00/09122 and WO 00/09123. Additional ways to get orlistat disclosed in European patent applications EP 185359, 189577, 443449 and 524495.

Preferably orlistat is introduced orally in a dose of from 60 to 720 mg per day in split doses two or three times a day. Preferably the subject is injected dose of 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor, preferably in separate doses two or, particularly, three times a day. The subject is preferably a full or fat people, or people with a body mass index of 25 or higher. In General, preferably, the lipase inhibitor was administered approximately one or two hours after a meal containing fat. In General, for the conduct of certain of the above lipase inhibitor, preferably, that treatment was conducted for a person with hereditary obesity and body mass index of 25 or higher.

Orlistat may be people in conventional oral compositions, such as tablets, coated tablets, hard and soft gelatine capsules, emulsions or suspensions. Examples of media that can be used for tablets, coated tablets, dragées and hard gelatin capsules are lactose, other sugars and sugar alcohols like sorbitol, mannitol, maltodextrin or other fillers; surfactants-acceptable substances, like lauryl sulfate, Brij 96 or Tween 80; dezintegriruetsja substances, like nitroglicerina starch, corn starch or its derivatives; polymers, like povidone, crosspovidone; talc; stearic acid or its salts and other Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like additionally, the pharmaceutical compositions can contain preserving agents, solubilization, stabilizing agents, moisturizing agents, emulsifiers agents, sweetening agents, colorants, odorants, salts for modifying the osmotic pressure, buffers, covering agents and antioxidants. They may also contain other therapeutically useful substances. The compositions can be is conveniently presented in unit dosage forms and may be obtained by any means, known in the pharmaceutical field. Preferably, orlistat is introduced in accordance with the formulation shown in the examples and in the US 6004996, respectively.

The compounds of formula I can contain one or more asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric of racemates or mixtures diastereoisomeric racemate.

In the nomenclature used in this description, the atoms chineselanguage rings are numbered as follows:

Preferred are the compounds of formula I and their pharmaceutically active salts, especially the compounds of formula I.

Other preferred are the compounds of formula I, where R2represents alkyl, in particular methyl.

Other preferred are the compounds of formula I, where R3represents hydrogen.

Other preferred are the compounds of formula I, where R1represents-O-R4.

Other preferred are the compounds of formula I, where R1represents-N(R5)(R6).

Also preferred are the compounds of formula I, where R4represents hydrogen, aralkyl geterotsiklicheskikh or cycloalkenyl. Especially preferred are the compounds of formula I, where R4represents benzyl or pyridinylmethyl, substituted by cyano, fluorine or chlorine.

Preferred are the compounds of formula I in which R1represents-N(R5)(R6and one of R5or R6is hydrogen, and the second can be selected from alkyl, cycloalkyl, cycloalkenyl, alkylcarboxylic, cycloalkylcarbonyl, aryl, aralkyl, arylcarbamoyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, geterotsiklicheskikh, alkyl-SO2-, aryl-SO2-, heterocyclyl-SO2- or amino-SO2-.

Other preferred variants of implementation of the present invention are the compounds of formula I in which R5and R6independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or geterotsiklicheskikh. Especially preferred are the compounds of formula I in which R5or R6represents hydrogen, and the second represents alkyl, pyridinyl or fornicator.

Also preferred are the compounds of formula I, where a is a 5-7-membered saturated heterocyclic ring containing the nitrogen atom attached to hinazolinam ring, where the ring may be optionally substituted by one or not is how many deputies, preferably one Deputy, independently selected from halogen, alkyl, alkoxy, haloalkoxy, cycloalkylation, hydroxy, amino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, haloalkoxy and cycloalkylcarbonyl. Also preferred are the compounds of formula I, where a is a 5-6-membered saturated heterocyclic ring, preferably a 5-membered saturated heterocyclic ring containing the nitrogen atom attached to hinazolinam ring, where the ring may be optionally substituted by one or more substituents, preferably one Deputy, independently selected from halogen, alkyl, alkoxy, haloalkoxy, cycloalkylation, hydroxy, amino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, haloalkoxy and cycloalkylcarbonyl.

Another preferred embodiment of the present invention are the compounds of formula I where ring a is a 5-membered saturated heterocyclic ring containing the nitrogen atom attached to hinazolinam ring, where the ring And optionally substituted by one or more substituents, preferably one Deputy, selected from alkoxy, hydroxy or hydroxyalkyl. Especially preferred are the compounds of formula I in which ring a is a is pirrolidone or pyrrolidinyl, substituted alkoxy, hydroxy or hydroxyalkyl.

Most preferred are the compounds of formula I where ring a is pyrrolidinyl or pyrrolidinyl substituted by hydroxymethyl, methoxy or ethoxy.

Examples of compounds of formula (I) are

1. 7-benzyloxy-2-methyl-4-pyrrolidin-1-imaginaton;

2. 2-methyl-4-pyrrolidin-1-imaginaton-7-ol;

3. 4-(2-methyl-4-pyrrolidin-1-imaginaton-7-intoximeter)benzonitrile;

4. 7-(2-chloropyridin-3-ylethoxy)-2-methyl-4-pyrrolidin-1-imaginaton;

5. 2-(2-methyl-4-pyrrolidin-1-imaginaton-7-intoximeter)benzonitrile;

6. 7-(2-foroperation-3-ylethoxy)-2-methyl-4-pyrrolidin-1-imaginaton;

7. 5-(2-methyl-4-pyrrolidin-1-imaginaton-7-intoximeter)pyridine-2-carbonitrile;

8. 7 cyclopropylmethoxy-2-methyl-4-pyrrolidin-1-rhinetone hydrochloride;

9. 4-(2-methyl-4-pyrrolidin-1-imaginaton-7-yloxy)benzonitrile hydrochloride;

10. (S)-[1-(7-benzyloxy-2-methylpyrazole-4-yl)pyrrolidin-2-yl]methanol;

11. (S)-4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-ol;

12. (S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-intoximeter]benzonitrile;

13. (S)-{1-[7-(2-chloropyridin-3-ylethoxy)-2-methylpyrazole-4-yl]pyrrolidin-2-yl}methanol;

14. (S)-{1-[7-(2-foroperation-3-ylethoxy)-2-methylpyrazole-4-yl]pyrrolidin-2-yl}methanol;

15. (S)-5-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-metalfinish the in-7-intoximeter]pyridine-2-carbonitrile;

16. (S)-[1-(7-cyclopropylmethoxy-2-methylpyrazole-4-yl)pyrrolidin-2-yl]methanol;

17. (S)-7-benzyloxy-4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole;

18. (S)-4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-ol;

19. (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-intoximeter]benzonitrile;

20. (S)-1-(7-benzyloxy-2-methylpyrazole-4-yl)pyrrolidin-3-ol;

21. (S)-4-(3-hydroxypyrrolidine-1-yl)-2-methylpyrazole-7-ol;

22. (S)-4-[4-(3-hydroxypyrrolidine-1-yl)-2-methylpyrazole-7-intoximeter]benzonitrile hydrochloride;

23. cyclopropylmethyl-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine;

24. isobutyl-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine;

25. (2.2-dimethylpropyl)-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine;

26. (2-Chlorobenzyl)-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine;

27. (2-methylbenzyl)-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine;

28. 4-(2-methyl-4-pyrrolidin-1-imaginaton-7-ylamino)benzonitrile;

29. (4-forefeel)-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine;

30. (2-methyl-4-pyrrolidin-1-imaginaton-7-yl)pyridine-3-ylamine;

31. (2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amide, furan-2-carboxylic acid;

32. (S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-yl]pyridine-3-ylamine;

33. (S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-yl]-(4-forefeel)amine and

34. (S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-yl]pyridine-3-ylamine.

Primereniya preferred compounds of formula (I) are

4-(2-methyl-4-pyrrolidin-1-imaginaton-7-intoximeter)benzonitrile;

7-(2-chloropyridin-3-ylethoxy)-2-methyl-4-pyrrolidin-1-imaginaton;

7-(2-foroperation-3-ylethoxy)-2-methyl-4-pyrrolidin-1-imaginaton;

(S)-{1-[7-(2-chloropyridin-3-ylethoxy)-2-methylpyrazole-4-yl]pyrrolidin-2-yl}methanol;

(S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-intoximeter]benzonitrile;

isobutyl-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine;

(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)pyridine-3-ylamine;

(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amide, furan-2-carboxylic acid;

(S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-yl]pyridine-3-ylamine and

(S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-yl]pyridine-3-ylamine.

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

The substituents and symbols used in the following description of the methods have the meanings specified above, except where otherwise indicated.

Compounds of General formula Ia, where R1represents N(R5)(R6), can be obtained according to scheme 1 from compounds of General formula IIa (Hal denotes Cl, Br or I), containing substituents R2and R3and And that meet the above notations, reaction, such condensation by Buchwald, catalyzed by Pd from the corresponding amines, amides or sulfonamides, for example, with the use of the catalyst Pd(OAc) 2, BINAP (2,2 bis(diphenylphosphino)-1,1-binaphthyl) or Xanthphos as a chelating phosphine ligand, NaOtBu or cesium carbonate as the base, in a solvent such as toluene or dioxane, at a moderate temperature (S.L.Buchwald in: J. Am. Chem. Soc., 1996, s; ACE. Chem. Res., 1998, s; Org Lett., 2000, 2, s).

An alternative way of obtaining these compounds is the reaction Ullman, dioxane or DMF in the presence of chloride or iodide, copper(I), similarly to the method described S.L.Buchwald (J. Am. Chem. Soc., 2001, s).

Alternatively, compounds of General formula Ia can be obtained from compounds of General formula IIb according to scheme 2, using a suitable sequence of reactions alkylation relevant halogenation in the presence of a base such as sodium hydride in THF or DMSO. For derivatives, in which R5, R6represents aryl or heteroaryl, you can use the reactions of education C/N connection type condensation Buchwald, catalyzed by Pd, or condensation on Ullman, aryl - and heteroarylboronic as described above. Compounds in which R5, R6is alkylsulphonyl, arylcarbamoyl, heterocalixarenes, aryl-, heteroaryl-, alkyl - or amino - sulfonyl, can be obtained from compounds of General formula IIb reaction acylation or sulphonation applied to the respective acylhalides or sulphonylchloride in the presence of a base, for example, DMAP or triethylamine in solvents such as THF or DMF or methylene chloride. Hal figure 2 denotes chlorine, bromine or iodine. For compounds in which R2is an amine, the introduction of protective groups for the amino group to the above reactions is preferred. This can be achieved, for example, by acylation of an amino group (for example, acetylchloride) of the appropriate intermediate compounds in the reaction scheme below, using standard conditions known in the prior art. The acyl group may subsequently be removed by hydrolysis.

Compounds of General formula Ib, in which R1represents O-R4can be obtained according to scheme 3 from compounds of General formula IIc, containing substituents R2and R3that fit the above definition, the reaction of alkylation or sulfonation using appropriate Gulidov or sulphonylchloride, in the presence of a base, For example, a2CO3, in a suitable solvent, for example DMF. When changing the sequence of reactions possible introduction of the radical R4in suitable intermediate in the reaction sequence below, prior to the introduction of substituents on the 4-th position of the quinoline.

Compounds of General formula Ib can also be obtained according to scheme 3 from compounds of General formula IIa with appropriate alcohols R4HE response education/communication, catalyzed by Pd, using, for example, Pd(OAc)2as a catalyst, 2-(di-tert-butylphosphino)-1,1'-binaphthyl as a ligand, Cs2CO3as grounds, toluene as a solvent (the same technique: S.L.Buchwald, J. Am. Chem. Soc., 2001, 123, s). An alternative way of obtaining a condensation Ullman using, for example, iodide Cu(I) as a catalyst, Cs2CO3as grounds, toluene as solvent, in the presence of catalytic amounts of 1,10-phenanthroline, similar to the previously described method S.L.Buchwald (Org. Letters, 2002, s).

The method of obtaining compounds of General formula IIa is presented in schemes 4 and 5.

In the case of compounds in which R2represents alkyl, according to scheme 4, the starting compounds are the corresponding derivatives of 2-aminobenzoic acid IIIa, which is previously described in the prior art or can be obtained by standard methods. The following stages of the reaction are carried out according to known standard methods. Thus, the reaction of compounds of General formula IIIa with chlorides alkalicarbonate acid in the presence of tertiary amines, for example t is ethylamine, catalytic amounts of 4-dimethylaminopyridine (DMAP) and ammonium carbonate in DMF leads to obtaining appropriate hintline General formula IVa. An alternative method of preparing compounds IVa is the reaction of compounds IIIa with relevant alkylenediamine in a solvent, for example methanol, in the presence of a base, such as triethylamine, at the boiling temperature of the reaction mixture. The transformation into the corresponding chlorination derivatives of the General formula Va is carried out using POCl3when the boiling temperature of the reaction mixture, optionally in the presence of N,N-dimethylaniline, according to standard methods described in the prior art. Subsequent reaction with the corresponding amines indicated above, or with the use of a large excess of amine without solvent or using 2-fold excess amine in a suitable solvent, such as N-organic, xylene, ethanol or THF, optionally in the presence of catalytic amounts of NaI, using pyridine as a base leads to the formation of compounds of General formula IIa and IIc (after removal of benzyl ester by hydrogenation). Compounds of General formula IIb can be obtained from compounds of General formula IIa by reaction of condensation with benzophenone catalyzed by palladium, followed by hydrolysis according to the method of isonomy S.L.Buchwald (Tetrahedron Lett., 1997, s).

Compounds of General formula IIa, in which R2represents NH2or amino, can be obtained according to scheme 5. Thus, the esters of 2-aminobenzoic acid of General formula IIIb (or similar derivatives) can be turned into hintline General formula IVb processing hydrochloride of chloropromazine in DMSO as a solvent (the same reaction, see: J. Med. Chem., 1990, s) or by reaction with cyanamide in the presence of HCl, followed by treatment with a base, for example NaOH (analogous reaction, see: J. Med. Chem., 2000, s). NH2group in compounds IVb can then be selectively proaccelerin reaction with the appropriate alkylated by known methods, leading to compounds of General formula IVc. Another method of preparing compounds IVc reaction of compounds IIIb with substituted cyanamide or Chloroaniline presented in figure 5. The sequence of transformations of compounds of General formula IVb and IVc in compounds of General formula IIa, in which R2represents amino presented in figure 4.

The conversion of compounds of General formula I, pharmaceutically acceptable salts may be carried out by the processing of such compounds, inorganic acid, for example, halogen acid, such as, for example, hydrochloric acid, bromine is standardna acid, sulfuric acid, nitric acid, phosphoric acid, etc. or by treatment with an organic acid, e.g. acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate, n-toluensulfonate. When processing compounds of General formula I with physiologically compatible bases, you can also receive the corresponding salts of carboxylic acids.

The conversion of compounds of General formula I into the corresponding pharmaceutically acceptable esters or amides can be carried out, for example, treatment with a suitable amino - or hydroxyl groups present in the molecules of carboxylic acid, e.g. acetic acid, with the use of condensing reagent, for example, hexafluorophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF) or N,N-dicyclohexylcarbodiimide (DCCI) to obtain the ester of carboxylic acid or carboxylic acid amide.

A preferred method of preparing compounds of formula I includes one of the following reactions:

a) the reaction of compounds of General formula IIa with R6(R5)NH with obtaining compounds of General formula Ia

where the radicals R2, R3, R5, R6and a have the meanings indicated above, a Hal denotes chlorine, bromine or iodine;

b) reaction of compounds of General formula IIb with R 5-Hal and/or R6-Hal obtaining compounds of General formula Ia

where the radicals R2, R3, R5, R6and a have the meanings indicated above, a Hal denotes chlorine, bromine or iodine;

C) the reaction of compounds of General formula IIc with R4-Hal obtaining compounds of General formula Ib

where the radicals R2, R3, R4and a have the meanings indicated above, a Hal denotes chlorine, bromine or iodine;

g) the reaction of compounds of General formula IIa with R4HE obtaining compounds of General formula Ib

where the radicals R2, R3, R4and a have the meanings indicated above, a Hal denotes chlorine, bromine or iodine.

Preferred intermediate compounds are:

7-benzyloxy-4-chloro-2-methylpyrazole;

7-bromo-2-methyl-4-pyrrolidin-1-imaginaton;

(S)-7-bromo-4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole and

(S)-7-bromo-4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole.

Another object of the invention is also the compounds of formula I, described above, for use as pharmaceutically active substances.

It is also an object of the invention is the above-described compounds to obtain drugs for the prevention and treatment of diseases caused by disorders associated with cocktail recipes. what Ohm NPY, especially for medicines for the prevention and treatment of arthritis, diseases of cardiovascular system, diabetes, renal failure and particularly eating disorders and obesity.

It is also an object of the invention are pharmaceutical compositions containing a compound of the formula I described above and a therapeutically inert carrier.

The object of the invention is also the use of the above compounds to obtain drugs, especially for the treatment and prevention of arthritis, diseases of cardiovascular system, diabetes, renal failure and particularly eating disorders and obesity.

Another object of the invention are compounds obtained in accordance with one of the above methods.

Another object of the invention is a method for the treatment and prevention of arthritis, diseases of cardiovascular system, diabetes, renal failure and particularly eating disorders and obesity, which consists in the introduction of an effective amount of the above compounds.

The next aspect of the invention is a method of treating obesity in humans in need of such treatment, which comprises administration to a human a therapeutically effective amount of the compounds of formula I and a therapeutically effective amount of the inhibitor is ipaz, particularly preferably, where the lipase inhibitor is orlistat. It is also an object of the present invention is the above-mentioned method in which introduction can be carried out simultaneously, separately or sequentially.

Another preferred embodiment of the present invention is the use of compounds of formula I for the manufacture of a medicinal product for the treatment and prevention of obesity in patients also treated with the lipase inhibitor, particularly preferably with orlistat.

Another object of the invention is also the above-described compounds for the production of pharmaceuticals for the treatment and prevention of alcoholism.

Another object of the invention is a method for the treatment and prevention of alcoholism.

Methods of analysis

Cloning of cDNA NPY5 receptor mice:

Whole cDNA encoding the NPY5 receptor mouse (mNPY5) amplified from cDNA of mouse brain using specific primers designed based on the published literature sequence, and Pfu DNA polymerase. The amplification product was subcloned into the expression vector pcDNA3 mammalian using the restriction sites Eco RI and XhoI. Positive clones sequenced and one clone that encodes a known published sequence was selected for further manufacture of the article is stable cell clones.

Stable transfection:

Cells of the human embryo kidney 293 (NEC) were subjected to transfection with 10 μg mNPY5 DNA with the use of lipofectamine. Two days after transfection initiated the selection of geneticin (1 mg/ml) and selected several stable clones. One of the clones was further used for pharmaceutical characteristics.

Competitive binding of radioactively labeled ligands:

Cells of the human embryo kidney 293 (NEC)expressing recombinant NPY5 receptor mouse (mNPY5), destroyed three-cycle freeze/thaw in hypotonic Tris buffer (5 mm, pH 7.4, 1 mm MgCl2), then homogenized and centrifuged at 72,000 rpm for 15 minutes. The precipitate was twice washed in 75 mm Tris buffer, pH 7.4, containing 25 mm MgCl2that'll get 250 mm, 0.1 mm of phenylmethylsulfonyl and 0.1 mm 1,10-phenanthroline, suspended in the same buffer, and aliquots were stored at -80°C. Protein was determined by the method of Lowry, using as a standard of bovine serum albumin (BSA).

Study competitive binding of radioactively labeled ligands were carried out in 250 μl of 25 mm Hepes buffer (pH 7.4, 2.5 mm CaCl2I mm MgCl2, 1% bovine serum albumin and 0.01% NaN3)containing 5 μg of protein, 100 PM [125I] - labeled peptide YY (PYY) and 10 μl of DMSO containing C is acetelyne the number of unlabeled test compounds. After incubation for 1 hour at 22°bound and free ligands were separated by filtration through filters made of fiberglass. Nonspecific binding was assessed in the presence of 1 μm unlabeled PYY. Specific binding was determined as the difference between total binding and nonspecific binding. The values of the IC50was defined as the concentration of antagonist that displaces 50% of the binding of [125I] - labeled neuropeptide Y. These values were determined by linear regression analysis after translating data binding in logit/log values.

The results obtained in the described test using some of the compounds according to the invention as tested compounds presented in the table below:

ConnectionNPY5-R (mouse) IC50(nm)
39
243

The preferred compounds described above, had values IC50less than 1000 nm; more preferred compounds possessed values IC50less than 100 nm, in special cases less than 10 nm. The most preferred compounds possessed values IC50less than 2 nm. These results were obtained by applying the above test.

Compounds of General formula I and their pharmaceutically p is ielemia salts and esters can be used as drugs (e.g., in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, for example, orally (for example, in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, syrups, emulsions or suspensions), nasal (e.g., in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the introduction can also be carried out parenterally, for example intramuscularly or intravenously (for example, in the form of solutions for injection).

Compounds of General formula I and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert inorganic or organic adjuvants to obtain tablets, coated tablets, dragées and hard gelatin capsules. As such adjuvants to obtain tablets, coated tablets and hard gelatin capsules can be used, for example, lactose, corn starch and its derivatives, talc, stearic acid or its salts, etc.

Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substance, liquid polyols etc

Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable adjuvants to obtain solutions for injection are the Xia, for example, water, alcohols, polyols, glycerol, vegetable oils etc.

Suitable adjuvants to obtain candles are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, substances that increase the viscosity stabilizers, moistening agents, emulsifiers, sweeteners, colorants, odorants, salts, influencing osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

In accordance with the present invention compounds of General formula I and their pharmaceutically acceptable salts can be used for the prevention and treatment of arthritis, diseases of cardiovascular system, diabetes, renal failure and particularly eating disorders and obesity. The dose can vary within a wide range and, of course, must be installed in accordance with the individual requirements in each particular case. In General, in the case of oral administration the dose is from 0.1 mg to 20 mg per kg body weight, preferably from 0.5 mg to 4 mg per kg (about 300 mg for humans), preferably divided into 1-3 separate doses, which may include, if necessary, from the same quantities of the. Should, however, be understood that the above upper limit can be exceeded if necessary.

The invention is illustrated by examples that do not have restrictive.

Examples

Example 1

a) a Solution of 0.44 g (1.55 mmol) 7-benzyloxy-4-chloro-2-methylinosine 1.9 ml (23.2 mmol) of pyrrolidine boiled under reflux for 17 hours in an argon atmosphere. The reaction mixture was concentrated in vacuo, the residue was applied onto a column of silica gel, was suirable CH2Cl2/MeOH (98:2 to 95:5). The obtained fractions were combined and concentrated in vacuum, obtaining 0.31 g (58,7%) target 7-benzyloxy-2-methyl-4-pyrrolidin-1-rhinetone in the form of a viscous yellow oil. ISP mass spectroscopy, m/e: 320,4 (M+1 calculated for C20H21N3About: 320).

Obtaining initial connection:

b) a Suspension of 1.1 g (5,64 mmol) of 2-acetylamino-4-hydroxybenzoic acid (receive: Recl. Trav. Chim. Pays-Bas, 1953, 72, s), 1.6 ml (13,53 mmol) benzylchloride, 3,9 g (as opposed to 28.18 per mmol) of potassium carbonate in DMF (15 ml) was stirred for 17 hours at 80°C in argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was transferred into a mixture of CH2Cl2and water. After separation of the layers the aqueous layer once was extracted with CH2Cl2organic layers were combined, washed with saturated solution of NaCl, dried over MgSO4and to whom is centered in the vacuum, getting 1,89 g (85,75%) target benzyl ester 2-acetylamino-4-benzyloxybenzyl acid as a colourless powder. ISP mass spectroscopy, m/e: 376,5 (M+1 calculated for C23H21NO4: 375,42).

C) a Suspension of 1.87 g (to 4.98 mmol) of benzyl ester 2-acetylamino-4-benzyloxybenzyl acid in EtOH (20 ml) was treated with 1N NaOH (20-30 ml) and stirred at 95°C-130°C (oil bath) until complete reaction according to TLC and NMR (reaction time about 34 hours). The reaction mixture was cooled to room temperature, the pH value was brought to pH 6 by addition of 1N aqueous HCl, the precipitate was filtered and dried under high vacuum, receiving 1.19 g (91,7%) target 2-amino-4-benzyloxybenzyl acid as a colourless powder. ISP mass spectroscopy, m/e: 242,2 (M+1 calculated for C14H13NO3: 242).

g) To a solution of 0,695 g (5,62 mmol) of the hydrochloride of ethylacetoacetate in the Meon (16 ml) under stirring at room temperature was added 0,82 ml (5,86 mmol) of triethylamine, after 5 minutes was added to 1.14 g (4,69 mmol) 2-amino-4-benzyloxybenzyl acid. The reaction mixture is boiled under reflux for 5 hours, then cooled to room temperature, the precipitate was filtered and dried under high vacuum, obtaining 0.9 g (69,4%) target 7-benzyloxy-2-methyl-1H-hinzelin-4-it is in the form of a white powder. ISP is ACC-spectroscopy, m/e: 267,3 (M+1 calculated for C16H14N2O2: 267).

d) a Suspension of 0.9 g (3,38 mmol) 7-benzyloxy-2-methyl-1H-hinzelin-4-she POCl3(4.6 ml, 50 mmol) was boiled under reflux for 1.5 hours. The reaction mixture was concentrated in vacuo, the residue was transferred into a mixture of CH2Cl2and cold dilute solution of NaHCO3(pH 7-8). After separation of the layers the aqueous layer was twice extracted with CH2Cl2. The combined organic fractions were washed with saturated solution of NaHCO3saturated NaCl solution, dried over Mg2SO4. The solvent is kept in vacuum, obtaining 0.45 g (47.2%) of crude 7-benzyloxy-4-chloro-2-methylinosine in the form of dark red wax-like solid, which without further purification was used in the next stage. Rf: 0,9 (CH2Cl2/Meon: 9/1; original connection Rf: 0,7).

Example 2

To a suspension 0,255 g (0.8 mmol) 7-benzyloxy-2-methyl-4-pyrrolidin-1-rhinetone, obtained as described in example 1, in the Meon (5 ml) was added 75 mg of palladium on coal (10%) and was first made at room temperature for 2 hours, until the reaction is completed according to HPLC. The catalyst was filtered, the filtrate was concentrated in vacuum. The precipitation was filtered and dried under high vacuum, getting to 0.19 g (98%) of 2-methyl-4-pyrrolidin-1-imaginaton-7-ol is in the form of a yellow powder. ISP mass spectroscopy, m/e: 230,2 (M+1 calculated for C13H15N3A: 230).

Example 3

A mixture of 90 mg (0.4 mmol) 2-methyl-4-pyrrolidin-1-imaginaton-7-ol as described in example 2, 130 mg (0,94 mmol) of potassium carbonate and 92 mg (0.47 mmol) of 4-(methyl bromide)benzonitrile in DMF (4 ml) was heated at 100°C for 2.5 hours in an argon atmosphere. The reaction mixture was cooled to room temperature, poured into ether (40 ml) and was stirred for 5 minutes. The precipitation was filtered, washed with water, ether and dried in high vacuum, getting 108 mg (75,2%) of 4-(2-methyl-4-pyrrolidin-1-imaginaton-7-intoximeter)benzonitrile in the form of light yellow powder. ISP mass spectroscopy, m/e: 345,4 (M+1 calculated for C21H20N4O: 345).

Example 4

Similarly to the method described in example 3 by reaction of 2-methyl-4-pyrrolidin-1-imaginaton-7-ol with 2-chloro-3-chloromethylpyridine was obtained 7-(2-chloropyridin-3-ylethoxy)-2-methyl-4-pyrrolidin-1-imaginaton in the form of a light brown powder. ISP mass spectroscopy, m/e: 355,3 (M+1 calculated for C19H19ClN4O: 355).

Example 5

Similarly to the method described in example 3 by reaction of 2-methyl-4-pyrrolidin-1-imaginaton-7-ol with 2-bromomethylbiphenyl received 2-(2-methyl-4-pyrrolidin-1-imaginaton-7-intoximeter)benzonitrile in the form of colorless powder. ISP mass spectroscopy, m/e: 345,4 (M+1 calculated for C 21H20N4O: 345).

Example 6

Similarly to the method described in example 3 by reaction of 2-methyl-4-pyrrolidin-1-imaginaton-7-ol with 3-chloromethyl-2-herperidin was obtained 7-(2-pererenan-3-ylethoxy)-2-methyl-4-pyrrolidin-1-imaginaton in the form of a light brown powder. ISP mass spectroscopy, m/e: 339,3 (M+1 calculated for C19H19FN4O: 339).

Example 7

Similarly to the method described in example 3 by reaction of 2-methyl-4-pyrrolidin-1-imaginaton-7-ol with 5-chloromethylpyridine-2-carbonitrile received 5-(2-methyl-4-pyrrolidin-1-imaginaton-7-intoximeter)pyridine-2-carbonitrile in the form of a light brown powder. ISP mass spectroscopy, m/e: 346,4 (M+1 calculated for C20H19N5O: 346).

Example 8

Similarly to the method described in example 3 (with the separation of the desired product as hydrochloride), the reaction of 2-methyl-4-pyrrolidin-1-imaginaton-7-ol with cyclopropanemethylamine received hydrochloride 7-cyclopropylmethoxy-2-methyl-4-pyrrolidin-1-rhinetone in the form of a white powder. ISP mass spectroscopy, m/e: 284,2 (M+1 calculated for C17H21N3About: 284).

Example 9

Similarly to the method described in example 3 (with the separation of the desired product as hydrochloride), the reaction of 2-methyl-4-pyrrolidin-1-imaginaton-7-ol with 4-bromobenzonitrile received hydrochloride 4-(2-methyl-4-pyrrolidin-1-imaginaton-7-yloxy)benzonitrile is in the form of a white powder. ISP mass spectroscopy, m/e: 331,3 (M+1 calculated for C20H18N4O: 331).

Example 10

Similarly to the method described in example 1, the reaction of 7-benzyloxy-4-chloro-2-methylinosine with an excess of (S)-2-(hydroxymethyl)pyrrolidine (a 2.5 molar equivalents) in 1-methyl-2-pyrrolidone as solvent at 100°received (S)-[1-(7-benzyloxy-2-methylpyrazole-4-yl)pyrrolidin-2-yl]methanol as a light brown oil. ISP mass spectroscopy, m/e: 350,5 (M+1 calculated for C21H23N3O2: 350).

Example 11

Similarly to the method described in example 2, the hydrogenation of (S)-[1-(7-benzyloxy-2-methylpyrazole-4-yl)pyrrolidin-2-yl]methanol as described in example 10, in the presence of Pd on coal (10%) in the Meon, was obtained (S)-4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylisatin-7-ol as a viscous light yellow oil. ISP mass spectroscopy, m/e: 260,3 (M+1 calculated for C14H17N3O2: 260).

Example 12

Similarly to the method described in example 3, reaction of (S)-4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-ol as described in example 11, 4-bromomethylbiphenyl was obtained (S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-intoximeter]benzonitrile in the form of a light yellow foam. ISP mass spectroscopy, m/e: 375,4 (M+1 calculated for C22H22N4O2: 375).

Example 13

Similarly to the method described in the example 3, the reaction of (S)-4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-ol as described in example 11, with the hydrochloride of 2-chloro-3-chloromethylpyridine was obtained (S)-{1-[7-(2-chloropyridin-3-ylethoxy)-2-methylpyrazole-4-yl]pyrrolidin-2-yl}methanol as colorless powder. ISP mass spectroscopy, m/e: 385,3 M+1 calculated for C20H21ClN4O2: 385).

Example 14

Similarly to the method described in example 3, reaction of (S)-4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-ol as described in example 11, with the hydrochloride of 2-fluoro-3-chloromethylpyridine was obtained (S)-{1-[7-(2-herperidin-3-ylethoxy)-2-methylpyrazole-4-yl]pyrrolidin-2-yl}methanol as a white powder. ISP mass spectroscopy, m/e: 369,4 (M+1 calculated for C20H21FN4O2: 369).

Example 15

Similarly to the method described in example 3, reaction of (S)-4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-ol as described in example 11, 5-chloromethylpyridine-2-carbonitrile was obtained (S)-5-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-intoximeter]pyridine-2-carbonitrile in the form of a white powder. ISP mass spectroscopy, m/e: 376,4 (M+1 calculated for C21H21N5O2: 376).

Example 16

Similarly to the method described in example 3, reaction of (S)-4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylpyrazole-7-ol as described in example 11, with cyclopropanemethylamine was obtained (S)-[1-(7-cyclo is reprotoxic-2-methylpyrazole-4-yl)pyrrolidin-2-yl]methanol as a white powder. ISP mass spectroscopy, m/e: 314.4 M. (M+1 calculated for C18H23FN3O2: 314).

Example 17

Similarly to the method described in example 1, the reaction of 7-benzyloxy-4-chloro-2-methylinosine with an excess of (S)-3-ethoxypyrrolidine (a 2.5 molar equivalents) in 1-methyl-2-pyrrolidone as solvent at 100°received (S)-7-benzyloxy-4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole in the form of a yellow powder. ISP mass spectroscopy, m/e: 364,3 (M+1 calculated for C22H25N3O2: 364).

Example 18

Similarly to the method described in example 2, the hydrogenation of (S)-7-benzyloxy-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine described in example 17, in the presence of Pd catalyst on coal (10%) in the Meon was obtained (S)-4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-ol as a viscous light yellow powder. ISP mass spectroscopy, m/e: 274,3 (M+1 calculated for C15H19N3O2: 274).

Example 19

Similarly to the method described in example 3, reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-ol as described in example 18, 4-bromomethylbiphenyl was obtained (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-intoximeter]benzonitrile in the form of colorless powder. ISP mass spectroscopy, m/e: 389,3 (M+1 calculated for C23H24N4O2: 389).

Example 20

Similarly to the method described in example 1, the reaction of 7-gasoline is hydroxy-4-chloro-2-methylinosine with an excess of (S)-3-hydroxypyrrolidine (a 2.5 molar equivalents) in 1-methyl-2-pyrrolidone as solvent at 100° With received (S)-1-(7-benzyloxy-2-methylpyrazole-4-yl)pyrrolidin-3-ol as a yellow powder. ISP mass spectroscopy, m/e: 336,3 (M+1 calculated for C20H21N3O2: 336).

Example 21

Similarly to the method described in example 2, the hydrogenation of (S)-1-(7-benzyloxy-2-methylpyrazole-4-yl)pyrrolidin-3-ol as described in example 20, in the presence of Pd on coal (10%) in the Meon was obtained (S)-4-(3-hydroxypyrrolidine-1-yl)-2-methylpyrazole-7-ol as a light brown powder. ISP mass spectroscopy, m/e: 246,2 (M+1 calculated for C13H15N3O2: 246).

Example 22

Similarly to the method described in example 3 (with the separation of the desired product as hydrochloride) by the reaction of (S)-1-(7-benzyloxy-2-methylpyrazole-4-yl)pyrrolidin-3-ol as described in example 21, from 4-bromomethylbiphenyl received hydrochloride (S)-4-[4-(3-hydroxypyrrolidine-1-yl)-2-methylinosine-7-intoximeter]benzonitrile in the form of colorless powder. ISP mass spectroscopy, m/e: 361,3 (M+1 calculated for C21H20N4O2: 361).

Example 23

a) To a suspension of 0.15 g (0,513 mmol) 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone, 21,3 mg (0,034 mmol) and racemic BINAP, 3.8 mg (0,017 mmol) of palladium(II) acetate and 65.8 mg (0,685 mmol) tert-butyl sodium in toluene (8 ml) at room temperature was added 0,365 g (5,13 mmol) aminomethylpropanol, and the mixture was boiled under reflux in the atmosphere is fere argon for 20 hours. The reaction mixture was filtered through glass fiber filter paper and the filtrate was transferred into a mixture of EtOAc and water. After separation of the layers the organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was transferred to a column of silica gel, was suirable mixture of CH2Cl2/Meon/NH4HE (10:1:0,2). The combined fractions were concentrated in vacuum, receiving 68 mg (46,9%) target cyclopropylmethyl-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine as a viscous brown oil. ISP mass spectroscopy, m/e: 283,2 (M+1 calculated for C17H22N4: 283).

Obtaining initial connection:

b) To a solution of 1 g (4,63 mmol) 4-romancenovel acid (J. Org. Chem. 1997, 62, c.1240-1256), 50 mg (0,417 mmol) of 4-(dimethylamino)pyridine and of 2.58 ml (18.5 mmol) of triethylamine in dry DMF (5 ml) with 3°With water-ice bath in an atmosphere of argon was added dropwise 0,79 ml (11.1 mmol) of acetylchloride for 20 minutes. The reaction mixture was heated to 90°C for 3 hours, then portions over 10 minutes was added to 1.32 g (13,89 mmol) of ammonium carbonate and the mixture was stirred at the same temperature for 1 hour. After cooling, the reaction mixture was poured into water, the precipitated precipitate was filtered, washed with water and dried in vacuum, obtaining 1.1 g (99,4%) of 7-bromo-2-methyl-3H-hinzelin-4-it is in the form of a light brown powder. So the l> 191°C (decomp.). EI mass spectroscopy, m/e 240 (M calculated for C9H7BrN2O: 240).

C) To a suspension of 0.45 g (of 1.87 mmol) 7-bromo-2-methyl-3H-hinzelin-4-she of 0.48 ml of N,N-dimethylaniline was added to 1.41 ml (to 15.4 mmol) of phosphorus oxychloride, the reaction mixture was heated at 60°C for 2 hours. The reaction mixture was evaporated in vacuo, the residue was transferred into 20 ml of water, neutralized with 10 ml of saturated sodium bicarbonate solution and was extracted twice with 25 ml dichloromethane. The organic layer was washed with 25 ml water, 25 ml of saturated solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The residue was purified column chromatography on silica gel, using as eluent a mixture of heptane/ethyl acetate (2:1)to give 0.29 grams (59%) of 7-bromo-4-chloro-2-methylinosine in the form of orange powder. T square>82°C. EI mass spectroscopy, m/e 258 (M calculated for C9H6BrClN2: 258).

g) a Solution of 0.8 g (3.1 mmol) of 7-bromo-4-chloro-2-methylinosine in 2 ml of pyrrolidine boiled under reflux for 12 hours. The reaction mixture was concentrated in vacuo, the residue was transferred to a column of silica gel, was suirable mixture of CH2Cl2/Meon (95:5). The combined purified fractions were concentrated in vacuum, obtaining 1 g (100%) target 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone in the form of a solid powder. TPL 120-122°C. ISP mA is with spectroscopy, m/e: 292,2 (M+1 calculated for C13H14BrN3: 292).

Example 24

Similarly to the method described in example 23, the reaction of 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone with isobutylamino received isobutyl-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine as a light brown amorphous powder. ISP mass spectroscopy, m/e: 285,3 (M+1 calculated for C17H24N4: 284,4).

Example 25

Similarly to the method described in example 23, the reaction of 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone with 2,2-dimethylpropylene received (2,2-dimethylpropyl)-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine as a brown foam. ISP mass spectroscopy, m/e: 299,5 (M+1 calculated for C18H26N4: 298,43).

Example 26

Similarly to the method described in example 23, the reaction of 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone with 2 chlorobenzylamino received (2-Chlorobenzyl)-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine as a yellow powder. ISP mass spectroscopy, m/e: 353,3 (M+1 calculated for C20H21ClN4: 353).

Example 27

Similarly to the method described in example 23, the reaction of 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone with 2 methylbenzylamino received (2-methylbenzyl)-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine as a yellow powder. ISP mass spectroscopy, m/e: to 333.3 (M+1 calculated for C21H24N4: 333).

Example 28

Similarly, the method of the ke, described in example 23, the reaction of 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone 4-aminobenzonitrile received 4-(2-methyl-4-pyrrolidin-1-imaginaton-7-ylamino)benzonitrile in the form of light yellow powder. ISP mass spectroscopy, m/e: 330,4 (M+1 calculated for C20H19N5: 330).

Example 29

Similarly to the method described in example 23, the reaction of 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone 4-fornerino received (4-forfinal)-(2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amine as a dark brown powder. ISP mass spectroscopy, m/e: 323,4 (M+1 calculated for C19H19FN4: 323).

Example 30

Similarly to the method described in example 23, the reaction of 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone with 3-aminopyridine received (2-methyl-4-pyrrolidin-1-imaginaton-7-yl)pyridine-3-ylamine as a pale brown powder. ISP mass spectroscopy, m/e: 306,4 (M+1 calculated for C18H19N5: 306).

Example 31

To a suspension of 0.12 g (0.41 mmol) of 7-bromo-2-methyl-4-pyrrolidin-1-rhinetone, 3.9 mg (0,021 mmol) of copper iodide (I) and 0,267 g (0.82 mmol) of cesium carbonate in dioxane (5 ml) at room temperature in an argon atmosphere was added to 4.7 mg level (0.041 mmol) of TRANS-1,2-diaminocyclohexane and 0.18 g (1.6 mmol) 2-furamide, the reaction mixture is boiled under reflux for 20 hours. The reaction mixture was poured into a mixture of EtOAc and water, after separation of the layers org the organic fraction is washed twice with water, dried over sodium sulfate and concentrated in vacuum. The residue was applied onto a column of silica gel, was suirable a mixture of CH2Cl2/MeOH/NH4OH (9:1:0,5). The obtained purified fractions were concentrated in vacuum, receiving 29 mg (22%) (2-methyl-4-pyrrolidin-1-imaginaton-7-yl)amide, furan-2-carboxylic acid as a colourless powder. ISP mass spectroscopy, m/e: 323,4 (M+1 calculated for C18H18N4O2: 323).

Example 32

a) Analogously to the method described in example 23, by reaction of the hydrochloride of (S)-7-bromo-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine with 3-aminopyridine was obtained (S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-yl]pyridine-3-ylamine in the form of a grey powder. ISP mass spectroscopy, m/e: 350,5 (M+1 calculated for C20H23N5O: 350).

Obtaining initial connection:

b) Analogously to the method described in example 23d), the reaction of 7-bromo-4-chloro-2-methylinosine with an excess of (S)-3-ethoxypyrrolidine (a 2.5 molar equivalents) in 1-methyl-2-pyrrolidone as solvent at 140°received hydrochloride (S)-7-bromo-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine in the form of light yellow powder. ISP mass spectroscopy, m/e: 336,2 (M+1 calculated for C15H18BrN3O: 336).

Example 33

Similarly to the method described in example 23, by reaction of the hydrochloride of (S)-7-bromo-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine, is written in example 32b), 4-foroenlinea was obtained (S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-yl]-(4-forfinal)amine as a yellow foam. ISP mass spectroscopy, m/e: 367,3 (M+1 calculated for C21H23FN4O: 367).

Example 34

a) Analogously to the method described in example 23, the reaction of (S)-7-bromo-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine with 3-aminopyridine was obtained (S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-yl]pyridine-3-ylamine as colorless powder. ISP mass spectroscopy, m/e: 336,3 (M+1 calculated for C19H21N5O: 336).

Obtaining initial connection:

b) Analogously to the method described in example 23d), the reaction of 7-bromo-4-chloro-2-methylinosine with an excess of (S)-3-ethoxypyrrolidine (a 2.5 molar equivalents) in 1-methyl-2-pyrrolidone as solvent at 140°received hydrochloride (S)-7-bromo-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine in the form of a light orange powder. ISP mass spectroscopy, m/e: was 322.3 (M+1 calculated for C14H16BrN3O: 322).

Example

The compound of General formula I can be used as active ingredient to obtain a known manner tablets of the following composition, mg:

1 tablet
The active ingredient200
Microcrystalline cellulose 155
Corn starch25
Talc25
The hypromellose20
425

Example B

The compound of General formula I can be used as active ingredient for the production of the famous way of the capsules of the following composition, mg:

One capsule
The active ingredient100,0
Corn starch20,0
Lactose95,0
Talc4,5
Magnesium stearate0,5
220,0

1. Compounds of General formula I

where R1represents-O-R4or-N(R5)(R6);

R2represents alkyl;

R3represents hydrogen;

R4represents hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, pyridinylmethyl substituted by cyano or halogen, cycloalkenyl;

R5and R6independently selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, ar is carbonyl, alkoxyalkyl, hydroxyalkyl, pyridinyl, furanosterol or R5and R6together with the N atom to which they are attached, form a 5-to 10-membered heterocyclic ring, which optionally includes a second heteroatom selected from nitrogen or oxygen, and where the heterocyclic ring optionally substituted by one or more substituents, independently selected from alkyl or alkoxygroup;

A is a 5-7-membered saturated heterocyclic ring including the nitrogen atom attached to hinazolinam ring, and optionally a second heteroatom selected from oxygen, sulfur or nitrogen, where the ring And optionally substituted by one or more substituents independently selected from alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl,

and their pharmaceutically acceptable salts and esters.

2. Compounds according to claim 1, in which R2represents methyl.

3. Compounds according to claim 1 or 2, in which R1represents-O-R4.

4. Compounds according to claim 3 in which R4represents hydrogen, aralkyl, pyridinylmethyl substituted by cyano or halogen, or cycloalkyl.

5. Compounds according to claim 4, in which R4represents benzyl or pyridinylmethyl substituted by cyano, fluorine or chlorine.

6. Compounds according to claim 1 or 2, Kotor is x R 1represents-N(R5)(R6).

7. Compounds according to claim 6, in which R5and R6independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, pyridinyl or furanosterol.

8. Compounds according to claim 7, in which one of R5or R6represents hydrogen and the other represents alkyl, pyridinyl, fornicator.

9. Compounds according to claim 1, in which a represents a 5-membered saturated heterocyclic ring including the nitrogen atom attached to hinazolinam ring, where the ring And optionally substituted by one or more substituents independently selected from alkoxy, hydroxy or hydroxyalkyl.

10. Compounds according to claim 9, in which a represents pyrrolidinyl or pyrrolidinyl substituted by hydroxymethyl, methoxy or ethoxy.

11. Compounds according to claim 1, selected from the following:

4-(2-methyl-4-pyrrolidin-1-imaginaton-7-intoximeter)benzonitrile;

7-(2-chloropyridin-3-ylethoxy)-2-methyl-4-pyrrolidin-1-imaginaton;

7-(2-herperidin-3-ylethoxy)-2-methyl-4-pyrrolidin-1-imaginaton;

(S)-{1-[7-(2-chloropyridin-3-ylethoxy)-2-methylpyrazole-4-yl]pyrrolidin-2-yl}methanol and

(S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylpyrazole-7-intoximeter]benzonitrile.

12. The method of obtaining the compounds of formula I according to claim 1, where R1is the th-O-R 4that includes the interaction of the compounds of General formula IIc with the compound of the formula R4-Hal in the presence of a base to obtain the compounds of General formula Ib

where R2, R3, R4and As defined in claim 1, a, Hal denotes chlorine, bromine or iodine.

13. The method of obtaining the compounds of formula I according to claim 1, including the interaction of the compounds of General formula IIa

where R2, R3and As defined in claim 1, a, Hal denotes chlorine, bromine or iodine,

with the compound of the formula R6(R5)NH or with the compound of the formula R4-OH, where R4, R5and R6defined in claim 1, in the presence of Pd or Cu salt(I) as a catalyst in obtaining compounds of General formula I

where R1, R2, R3and As defined in claim 1.

14. Compounds according to one of claims 1 to 11 for use as therapeutically active substances with antagonistic activity against neuropeptide Y.

15. Compounds according to one of claims 1 to 11 to obtain drugs for the prevention and treatment of diseases caused by disorders associated with the NPY receptors.

16. Pharmaceutical composition having antagonistic activity against neuropeptide Y, aderasa the connection according to one of claims 1 to 11 and a therapeutically inert carrier.

17. Compounds according to one of claims 1 to 11 obtained by the method described in item 12 or 13.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

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

12 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (U): or its pharmaceutically acceptable salt wherein X is chosen from -NR1, sulfur atom (S); Y1 and Y2 represent oxygen atom (O); Z represents O; m = 0 or 1; A is chosen from a direct bond, (C1-C6)-alkyl; R1 is chosen from hydrogen atom (H), alkyl; R3 and R6 are chosen independently from H, alkyl, halogenalkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocycloalkyl-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or heterocycloalkyl; R4 is chosen from H, alkyl; R5 represents a bicyclic or tricyclic group comprising two or three ring structure wherein each of that comprises from 3 to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl wherein each ring structure is joined with the next ring structure through a direct bond, through -O-, through -S-, through (C1-C6)-alkyl, through (C1-C6)-heteroalkyl, through (C1-C6)-alkynyl, through carboxy-(C1-C6)-alkyl, or it is condensed with the next ring structure wherein heteroalkyl represents heteroatom-substituted alkyl comprising one heteroatom chosen from N, O and S. Also, invention describes compounds of formulae (Ib), (Ic) and (Id) given in the invention description, pharmaceutical composition and using these compounds in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

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

17 cl, 3 tbl, 17 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I): wherein X represents -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO2N(R6), -N(R7)SO2; m = 1 or 2; A is chosen from a direct bond, (C1-C6)-alkyl; R1 represents hydrogen atom (H); each R2 and R3 is chosen independently from H, alkyl, aryl, alkylaryl, arylalkyl; each R4 is chosen independently from H, (C1-C3)-alkyl; R6 is chosen from H, alkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, arylalkyl, heteroaryl-alkyl; R2 and R6 can join to form a ring comprising up to 7 ring atoms, or R3 and R6 can join to form a ring comprising up to 7 ring atoms, or R4 and R6 can join to form a ring comprising up to 7 ring atoms; R5 represents monocyclic, bicyclic or tricyclic group comprising one or two ring structures wherein each of that comprises up to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl and possibly substituted; when R5 represents bicyclic group then each ring structure is bound with the next ring structure through a direct bond, through -O-, through (C1-C6)-alkyl or condensed with this next ring structure; R7 is chosen from (C1-C6)-alkyl. Also, invention describes compound of the formula (II) given in the description, pharmaceutical compositions and using compound of the formula (I) or the formula (II) in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes and representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of inhibitors and pharmaceutical compositions.

20 cl, 3 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: chemistry of polymers, chemical technology.

SUBSTANCE: invention relates to sulfoxides or sulfones grafted on polymers, polymeric compositions, a method for grafting and method for stabilization of polymers. Invention describes polymers comprising a grafted compound of the formula (I): [R1-SOm]n-R-SOp-R2 (I) wherein total symbols have values given in cl. 1 of the invention claim and represents a composition comprising thereof, a method for grafting compound of the formula (I) on polymers and a method for stabilization of polymers. Polymers comprising grafted sulfoxides or sulfones possess high stability against oxidative, thermal, dynamic destruction caused by the light effect and/or destruction caused by ozone effect.

EFFECT: improved preparing method, improved and valuable properties of polymers.

14 cl, 14 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chromane of the formula (I): and its salts. Method involves direct reaction of 5-(4-fluorophenyl)pyridine-3-carbaldehyde of the formula (II): with 2-aminomethylchromane or its salts under reductive conditions resulting to formation of compound of the formula (I). Synthesized compound of the formula (I) is converted to one of its salts by treatment with acid. Method provides simplifying process based on decreasing amount of by-side products formed.

EFFECT: improved method of synthesis.

8 cl, 2 dwg, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a novel method for synthesis of functionally substituted fullerenes of the general formula (I): Method involves interaction of fullerene[60] with 1H-1,2,3-benzotriazol-1-N,N-dimethylmethaneamine in the presence of Cp2TiCl2 as a catalyst in argon atmosphere, in toluene medium, at temperature 140-160°C for 2-4 h. The yield of the end product is 68-89%. Proposed compounds can be used as chelate compounds, sorbents, biologically active compounds and in the development of material with required electronic, magnetic and optical properties.

EFFECT: improved method of synthesis, valuable properties of compounds.

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

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

9 cl, 2 tbl, 50 ex

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

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 1-91-methyl-2-(3,4-fullero[60]-pyrrolidinyl))-1H-1,2,4-triazole of the general formula (1): Method involves interaction of fullerene[60] with N-[(1,2,4-triazol-1-yl)methyl]-N,N-dimethylamine of the general formula: (R-CH2-N-(CH3)2 wherein R means taken in the mole ratio C60 : R-CH2-N-(CH3)2 = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as a catalyst taken in the amount 15-25 mole% relatively to fullerene[60], in argon atmosphere, in toluene medium as a solvent at temperature 140-160°C for 2-4 h. The end substance is prepared with the yield 78-86%. Compound of the formula (1) can be used as chelating agent, sorbent, biologically active compound and in the development of novel materials with required electronic, magnetic and optical properties.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: herbicides.

SUBSTANCE: invention relates to application of 2-diethylamino-6-methoxy-4-[(4'-ethoxycarnonyl-5'-methyl-1',2',3'-triazole)-1'yl]1,3,5,-triazine of formula as antidote against phytotoxic action of 2,4-dichlorophenoxyacetic acid herbicide onto germinated sunflower seeds.

EFFECT: more effective sunflower germ root length and hypocotyl elongation on background of phytotoxic 2,4-D herbicide action.

2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of bipiperidine of the formula (I): , wherein X means a direct bond, -CH2-, -CH2-CH2- or -CHR9-; R1 means optionally R10- and/or R11-substituted phenyl, optionally R10- and/or R11-substituted heteroaryl, N-oxide of optionally R10- and/or R11-substituted heteroaryl or optionally R10- and/or R11-substituted naphthyl; R2 has one of values given for R1, or it means optionally R10-substituted (C1-C6)-alkyl, optionally R10-substituted (C3-C6)-cycloalkyl, optionally R10-substituted adamantyl; R3 has one of values given for R1; each radical among R4, R5, R6 and R7 means hydrogen atom; R8 means hydrogen atom or (C1-C6)-alkyl; R9 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; R10 represents from 1 to 4 substitutes chosen independently from (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C2-C6)-alkoxyalkyl, (C1-C6)-halidealkyl, (C3-C6)-cycloalkyl, phenyl, heteroaryl, heteroaryl N-oxide, fluorine, chlorine, bromine, iodine atoms, hydroxyl, groups -OR9, -CONH2, -CONHR9, -CONR9R9, -COOH, -CF3, -CHF2, -CN, -NH2, -NHR9, -NHC(O)R9, -NR9C(O)R9; R11 represents two adjacent substitutes that form anellated 4-7-membered nonaromatic ring optionally comprising up to two heteroatoms chosen independently from nitrogen oxygen and sulfur atoms; Y means a direct bond, -C(O)-, -S(O2)-, -CH2-. Proposed compounds can be in free form as a salt. Compounds of the formula (I) and their salts possess antagonistic activity with respect to CCR5-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 6 tbl, 83 ex

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