Quinoline derivatives as neuropeptide y antagonists

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinoline that can be used as ligands of neuropeptide Y (NPY) receptors and being first of all as neuropeptide Y (NPY) antagonists. Invention describes compounds of the formula (I): wherein R1 means -O-R4 or -NR5R6; R2 means hydrogen atom, alkyl, alkoxy-group or halogen atom; R3 means alkyl or halogen atom; R means hydrogen atom, alkyl, phenyl, phenyl substituted with 1-3 substitutes chosen independently of one another from group comprising alkyl, cyano-group, trifluoromethyl, alkoxy-group, halogen atom, pyrrolidinylcarbonyl and nitro-group, alkoxyalkyl or heterocyclyl that means saturated or aromatic 4-10-membered heterocycle comprising one heteroatom chosen from nitrogen, oxygen atoms; R5 and R6 are chosen independently of one another from group comprising hydrogen atom, alkyl or phenyl; or R5 and R6 in common with nitrogen atom (N) to which they are added form 5-10-membered heterocyclic ring comprising nitrogen atom optionally; A1 means 5-7-membered saturated heterocyclic ring comprising nitrogen atom added to quinoline ring and the second nitrogen atom optionally and wherein ring is substituted optionally with 1-3 substitutes chosen independently of one another from group comprising alkyl, alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, tetrahydropyranyloxyalkyl and cycloalkylalkoxy-group; A2 means -CH2- or -C(O)- wherein alkyl individually or in combination means alkyl group with a direct chain that comprises 1-8 carbon atoms; and their pharmaceutically acceptable salts and alkyl esters. Also, invention describes methods for synthesis of compounds of the formula (I) and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 117 ex

 

The present invention relates to new quinoline derivative, which can be used as ligands of the receptor for neuropeptide Y (NPY), primarily as antagonists of neuropeptide Y (NPY).

The invention relates primarily to compounds of the formula I

where

R1denotes-O-R4or-NR5R6;

R2denotes hydrogen, alkyl, cycloalkyl, alkoxy, halogen, heterocyclyl or amino;

R3denotes hydrogen, alkyl, amino or halogen;

R4denotes hydrogen, alkyl, cycloalkyl, aryl, aralkyl, cycloalkenyl, alkoxyalkyl, hydroxyalkyl or heterocyclyl;

R5and R6independently from each other chosen from the series comprising hydrogen, alkyl, cycloalkyl, aryl, aralkyl, cycloalkenyl, alkoxyalkyl, hydroxyalkyl and heterocyclyl;

or R5and R6together with the N atom to which they are attached, form a 5-to 10-membered heterocyclic ring, optionally containing a second heteroatom selected from nitrogen, oxygen or sulfur, where the heterocyclic ring optionally substituted by one or more substituents, independently from each other selected from alkyl and alkoxygroup;

And1represents a 5-7 membered saturated heterocyclic ring which contains the nitrogen atom attached to hinolinovogo ring, and optionally a second heteroatom selected from oxygen, sulfur or nitrogen, where the ring is optionally substituted by 1-3 substituents, independently of one another selected from the series comprising alkyl, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, acetylamino, cyano, tetrahydropyranyloxy, cycloalkylcarbonyl;

And2denotes-CH2-or-C(O)-;

and their pharmaceutically acceptable salts and esters.

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

Neuropeptide Y is composed of 36 amino acid peptide that is widely distributed in the Central and peripheral nervous system. This peptide mediates many physiological responses through various subtypes of its receptor. Animal studies have allowed to establish that neuropeptide Y is a very strong incentive absorption of food, and it was demonstrated that activation of the Y5 receptor neuropeptide Y leads to hyperphagia and reduces thermogenesis. Thus, compounds that are antagonists of subtype Y5 Retz is ptor neuropeptide Y, can be used for the treatment of eating disorders, such as obesity and hyperphagia.

The modern approach involves medical intervention with the objective of reducing the weight or preventing an increase in body weight. This is achieved by affecting the mechanism of the regulation of appetite, mediated by the hypothalamus, an important area of the brain that provides the regulation of food intake. In the claimed invention, it was found that some species of animals neuropeptide Y (NPY) is in the Central nervous system one of the most powerful mediators of eating. Increasing levels of NPY leads to a marked increase absorption of food. Known evidence that different receptors, neuropeptide Y (NPY) play a role in the regulation of appetite and weight gain. The impact on these receptors, probably reduces appetite and, as a consequence, the weight gain. Reduce body weight and maintain it over a long period of time can have a favorable effect on associated with overweight risk factors, such as arthritis, cardiovascular disease and renal failure.

Thus, the compounds of formula I, their salts and esters can be used for prevention or treatment of arthritis, cardiovascular diseases, diabetes, renal failure and, above all violations of the power supply and obesity.

Objects of the present invention are the compounds of formula I and their aforementioned salts and esters per se and their use as therapeutically active substances, the method of obtaining these compounds, intermediates, pharmaceutical compositions, medicaments containing the said compounds, their pharmaceutically acceptable salts and esters, the use of the compounds, salts and esters for the prevention and/or treatment of diseases, especially for the treatment or prevention of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders, such as hyperphagia and especially obesity, and application of the compounds, salts and esters for the preparation of drugs intended for the treatment or prevention of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.

In the context of the present description, the term "alkyl", either individually or in combination, signifies an alkyl group with straight or branched chain, containing from 1 to 8 carbon atoms, preferably an alkyl group with straight or branched chain, containing 1 to 6 carbon atoms, and most preferably an alkyl group with straight or branched chain, which sod is RIT 1-4 carbon atoms. Examples1-C8alkyl group with straight or branched chain are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomers pentile, isomers of hexyl, isomers of heptyl and isomers of Attila, preferably methyl and ethyl and most preferably methyl.

The concept of "cycloalkyl, individually 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 first and foremost cyclopentyl.

The term "alkoxy", individually or in combination, refers to the group alkyl-O-, where the term "alkyl" has the above significance, 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 "aryl", individually or in combination, signifies a phenyl or naftalina group, preferably the phenyl group, which optionally bears one or more, preferably 1-3 substituent which is independently from each other chosen from the series including halogen, trifluoromethyl, amino, alkyl, alkoxy, aryloxy, alkylaryl, cyano, carbarnoyl, alkoxycarbonyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, hydroxy, nitro, heterocalixarenes etc. Preferred heterocalixarenes group is pyrrolidinecarbonyl. Preferred substituents of the aryl, preferably phenyl, independently from each other chosen from the series comprising halogen, trifluoromethyl, alkyl, alkoxy, cyano, nitro and pyrrolidin-C(O)-. Examples of aryl are 2-tianfeng, 3-tianfeng, 4-tianfeng, tryptophanyl, methoxyphenyl, horlander, triptoreline and delapril.

The concept of "aralkyl, individually or in combination, signifies an alkyl or cycloalkyl, as defined above, preferably an alkyl group in which one hydrogen atom is substituted by an aryl group as defined above. Preferred are benzyl, benzyl, substituted hydroxy, alkoxygroup or halogen, preferably fluorine.

The concept of "heterocyclyl, individually 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 and sulfur, the preferred is the tsya oxygen and especially nitrogen. If necessary, it can be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, exography 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, with preferred substituents are halogen, alkyl, cycloalkyl and alkoxygroup. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 3,4-dihydro-1H-ethenolysis, azepane or tetrahydropyranyl, and each of these rings may be substituted by alkyl. Most preferred are pyrrolidinyl, pyridinyl and tetrahydropyranyl primarily tetrahydropyran-2-yl. The concept of a 5-10-membered heterocyclic ring in the radicals R5and R6denotes a saturated, partially unsaturated, or aromatic 5-10 membered mono - or bicyclic a heterocycle, such as pyrrolidine, piperidine and piperazine.

The term "amino", individually or in combination, signifies a primary, secondary or tertiary amino group attached through a nitrogen atom, where the secondary amino group carries as a substituent alkyl or cycloalkyl, and the tertiary amino group carrying two identical or different substituent, such as alkyl or cycloalkyl or two replacing the Titel of the nitrogen together form a ring, for example, denotes-NH2methylamino, ethylamino, dimethylamino, diethylamino, methylethylamine, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino, diethylamino and particularly preferably a primary amino group.

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

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

The term "nitro", individually or in combination, refers to-NO2group.

Examples of pharmaceutically acceptable salts of the compounds of formula I are salts with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid; or organic acids, such as methanesulfonate acid, formic acid, acetic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. Preferred is oxalic acid. The compounds of formula I which have a free carboxyl group, can also form salts with physiologically compatible bases. Examples of such salts are salts of alkali metals, alkaline earth metals, ammonium and alkylammonium, such as salts of Na, K, CA or Tetramethylammonium. The connection is of the formula I can also be present in the form zwitterions. The preferred salts are the salts of oxalic acid, hydrochloric acid and formic acid.

The compounds of formula I may also be solvated, for example, gidrirovanny. Solvation can occur during cooking or can be, for example, a consequence of hygroscopic properties initially anhydrous compound of formula I (hydration). The term "pharmaceutically acceptable salt" also includes pharmaceutically acceptable solvate.

The term "pharmaceutically acceptable esters of compounds of formula I" means that compounds of General formula I can be derivateservlet on the functional groups with obtaining derivatives, which in vivo can be transformed back to the original connection. Examples of such compounds include physiologically acceptable and metabolically labile ester derivative, such as a complex methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. In addition, under the scope of the invention covered by any physiologically acceptable equivalents of the compounds of General formula I, similar metabolically labile esters, which may form a starting compound of General formula I in vivo.

For example, the COOH-group of compounds of formula I can be tarifitsirovana with the formation of ester. Examples of acceptable SL is mportant esters are complex alkalemia and Arakelova esters. The preferred esters are the methyl, ethyl, propyl, butyl and benzyl esters. Most preferred are difficult methyl and ethyl esters. Other examples of pharmaceutically acceptable esters are compounds of the formula I, in which the hydroxy-group can be tarifitsirovana with the formation of ester. Examples of such esters are formate, acetate, propionate, butyrate, isobutyrate, valerate, 2-methylbutyrate, isovalerate and N,N-dimethylaminoacetyl. The preferred esters are the acetate and N,N-dimethylaminoacetyl.

The term "lipase inhibitor" refers to compounds that can inhibit the activity of lipases, for example, gastric and pancreatic lipases, for Example, orlistat and lipstatin described in US 4598089, are effective inhibitors of lipases. Lipstatin is a naturally occurring product of microbial origin, and orlistat is obtained by hydrogenation of lipstatin. Other inhibitors of lipases include the class of compounds, which are usually designated as anglicani. Anglicani are analogues of orlistat (Mutoh and others, 1994). The term "lipase inhibitor" refers to a polymer that is associated with inhibitors of lipases, which are described, for example, in international patent application WO 99/34786 (firm Geltex Pharmaceuticals Inc.). the tee polymers are characterized by they include as substituents 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, which is used for the control or prevention of obesity and hyperlipidemia (see US 4598089, issued July 1, 1986, which describes methods of obtaining orlistat and US 6004996, which describes an acceptable pharmaceutical composition). Other acceptable pharmaceutical compositions are described, for example, in international patent applications WO 00/09122 and WO 00/09123. Other methods of obtaining orlistat described in the publication of European patent applications EP 185359, 189577, 443449 and 524495.

Orlistat preferably administered orally in the amount of 60-720 mg per day in divided doses 2-3 times a day. Preferably, the patient is given a day 180-360 mg lipase inhibitor, most preferably 360 mg, preferably as divided doses of two, or preferably three times a day. The patient preferably represents suffering from obesity or overweight person, i.e. the person from whom the index weight is 25 or more. As a rule, preferably a lipase inhibitor in the time of 1 the 2 h after ingestion of food containing fat. As a rule, the introduction of the above lipase inhibitor is preferably carried out by a person with a severe family history of obesity index and body weight of 25 or more.

Orlistat, you can enter the person in the form of 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 type of sorbitol, mannitol, maltodextrin, or other fillers; surfactants of the type of sodium lauryl, Brij 96 or Tween 80; openers type of matriptase starch, corn starch or derivatives; polymers of type povidone, crosspovidone; talc; stearic acid or its salts, etc. are Acceptable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like in Addition to also, the pharmaceutical composition can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, agents for coating and antioxidants. They may also contain other therapeutically CE the basic substance. The composition generally can be a standard dose and can be prepared using any methods known in the pharmaceutical industry. Preferably orlistat is administered in compositions given in the examples and in the US 6004996 respectively.

The compounds of formula I can have several asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomer, a mixture of diastereoisomers, diastereoisomeric the racemates or mixtures diastereoisomeric racemate.

As used in this description of the nomenclature of the ring atoms of the quinoline ring are numbered as follows:

where R3attached in position 2 and R2attached in position 6.

Preferred are the compounds of formula I and their pharmaceutically acceptable salts. Especially preferred are the compounds of formula I.

Preferred are the compounds of formula I, in which

R1denotes-O-R4or-NR5R6;

R2denotes hydrogen, alkyl, cycloalkyl, alkoxy, halogen, heterocyclyl or amino;

R3denotes hydrogen, alkyl, amino or halogen;

R4denotes hydrogen, alkyl, cycloalkyl, aryl, aralkyl, cycloalkyl is, alkoxyalkyl, hydroxyalkyl or heterocyclyl;

R5and R6independently from each other chosen from the series comprising hydrogen, alkyl, cycloalkyl, aryl, aralkyl, cycloalkenyl, alkoxyalkyl, hydroxyalkyl and heterocyclyl;

or R5and R6together with the N atom to which they are attached, form a 5-to 10-membered heterocyclic ring, optionally containing a second heteroatom selected from nitrogen, oxygen or sulfur, where the heterocyclic ring optionally substituted by one or more substituents, independently from each other selected from alkyl and alkoxy;

And1represents a 5-7 membered saturated heterocyclic ring with the nitrogen atom that is attached to the quinoline ring, and optionally a second heteroatom selected oxygen, sulfur or nitrogen, where the ring is optionally substituted by 1-3 substituents, independently of one another selected from the series comprising alkyl, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, acetylamino, cyano;

And2denotes-CH2-or-C(O)-;

and their pharmaceutically acceptable salts and esters.

Preferred are the compounds of formula I in which R2denotes hydrogen, alkyl, alkoxy or halogen. Especially preferred are the compounds of formula I in which R2denotes hydrogen and methyl. Most preferred are the compounds of formula I in which R2denotes hydrogen.

Also preferred are the compounds of formula I in which R1denotes-O-R4.

Another preferred object of the present invention are the compounds of formula I in which R1refers to-NR5R6.

Preferred are also the compounds of formula I in which R3denotes hydrogen, methyl, methylamino, dimethylamino or chlorine.

Preferred are also the compounds of formula I in which R3denotes hydrogen or alkyl. More preferably alkyl. Even more preferably methyl and ethyl. Most preferably methyl.

Preferred are also the compounds of formula I in which R4denotes hydrogen, alkyl, aryl, alkoxyalkyl or heterocyclyl. Especially preferred are the compounds of formula I in which R4denotes hydrogen, alkyl, alkoxyalkyl, pyridinyl, pyrrolidinyl, tetrahydropyranyl, phenyl, phenyl substituted by 1-3 substituents, independently of one another selected from the series comprising alkyl, cyano, trifluoromethyl, alkoxy, halogen, pyrrolidinylcarbonyl and nitro.

Especially preferred are the compounds of formula I in which R4denotes hydrogen, alkyl, alkoxyalkyl, pyridinyl, pyrrol dinil, phenyl, phenyl substituted by 1-3 substituents, independently of one another selected from the series comprising alkyl, cyano, trifluoromethyl, alkoxy, halogen, pyrrolidinylcarbonyl and nitro.

Preferred are the compounds of formula I in which R5and R6independently from each other chosen from the series comprising hydrogen, alkyl, aryl or alkoxyalkyl,

or R5and R6together with the N atom to which they are attached, form a 5-or 6-membered heterocyclic ring which optionally contains a second heteroatom selected from nitrogen or oxygen, and where the heterocyclic ring optionally substituted by one or more, preferably 1-3 substituents, independently from each other selected from alkyl and alkoxy. Examples 5-6-membered heterocyclic rings are pyrrolidine, piperidine and piperazine, preferably pyrrolidine and piperidine.

Preferred are also the compounds of formula I in which R5and R6independently from each other chosen from the series comprising hydrogen, alkyl, aryl or alkoxyalkyl,

or R5and R6together with the N atom to which they are attached, forms a 5-or 6-membered heterocyclic ring and where the heterocyclic ring optionally substituted by one or more, preferably 1-3 substituents, independently from each other is selected from alkyl and alkoxy.

Especially preferred are the compounds of formula I in which one of the radicals R5and R6denotes hydrogen, aryl or alkoxyalkyl, and the second denotes hydrogen or alkyl; or R5and R6together with the N atom to which they are attached, form a pyrolidine ring.

Preferred are also the compounds of formula I, in which And1represents a 5-7 membered saturated heterocyclic ring, which is a nitrogen atom attached to the quinoline ring, and optionally a second heteroatom selected from oxygen, sulfur and nitrogen, and where the ring is optionally substituted by a Deputy selected from the series comprising alkyl, hydroxy, hydroxymethyl, amino, alkoxy, tetrahydropyranyloxy or cycloalkylcarbonyl, preferably alkyl, amino, tetrahydropyranyloxy or cyclopropylmethoxy.

Preferred are also the compounds of formula I, in which And1represents a 5-7 membered saturated heterocyclic ring, which is a nitrogen atom attached to the quinoline ring, and optionally a second heteroatom selected from oxygen, sulfur and nitrogen, and where the ring is optionally substituted by a Deputy selected from the series comprising alkyl, hydroxy, hydroxymethyl, amino, or alkoxy, preferably alkyl or amino. Examples of such a 5-7 membered saturated the s heterocyclic rings are pyrrolidine, piperidine, ASEAN, piperazine and [1,4]diazepan. Especially preferred are the compounds of formula I, in which And1represents a 5-7 membered saturated heterocyclic ring, which is a nitrogen atom attached to the quinoline ring, and which ring is optionally present second nitrogen atom and where the ring is optionally substituted by alkyl or amino group.

Preferred are also the compounds of formula I, in which And1represents a 5-7 membered saturated heterocyclic ring, which is a nitrogen atom attached to the quinoline ring, where the ring is optionally present second heteroatom selected from oxygen, sulfur or nitrogen, and where the second nitrogen atom, which optionally is substituted by alkyl.

Another preferred object of the present invention are the compounds of formula I, in which And1means pyrolidine, piperidine, asianave, pieperazinove or [1,4]diazepinone ring, optionally substituted by alkyl, alkoxy, dialkylamino or hydroxyalkyl. Especially preferred are the compounds of formula I, in which And1means pyrolidine, piperidine, asianave, pieperazinove or [1,4]diazepinone ring, optionally substituted alkyl, dimethylaminopropoxy or hydroxymethyl. Preferred is entrusted are also the compounds of formula I, in which And1means pyrolidine, piperidine, asianave, pieperazinove, pyrolidine or [1,4]diazepinone ring optionally substituted by alkyl or amino group. Most preferred are the compounds of formula I, in which And1means pyrolidine, piperidine, asianave, 4-methylpiperazine, 3-dimethylaminopyridine or 4-methyl[1,4]diazepinone ring.

Preferred are also the compounds of formula I, in which And2denotes-CH2-.

Another preferred embodiment of the present invention are the compounds of formula I, in which A2is-C(O)-.

Examples of preferred compounds of formula I are:

1. 3-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

2. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol,

3. (4-azepin-1-yl-2-methylinosine-7-yl)methanol,

4. 3-(4-azepin-1-yl-2-methylinosine-7-ylethoxy)benzonitrile,

5. 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

6. 4-(4-azepin-1-yl-2-methylinosine-7-ylethoxy)benzonitrile,

7. 2-methyl-4-pyrrolidin-1-yl-7-(3-trifluoromethyl-phenoxymethyl)quinoline,

8. 2-methyl-4-pyrrolidin-1-yl-7-(4-triftormetilfullerenov)quinoline,

9. (2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)-(3-triptoreline)amine,

10. 2-methyl-7-phenoxymethyl-4-pyrrolidin-1-rhinolin,

11. 4-azepin-1-yl-2-methyl-7-(3-triftormetilfullerenov)quinoline,

12. 7-(3-methoxyphenoxy)-2-methyl-4-pyrrolidin-1-rhinolin,

13. 4-[(2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile,

14. 7-(2-methoxyphenoxy)-2-methyl-4-pyrrolidin-1-rhinolin,

15. 7-(2-forfinancial)-2-methyl-4-pyrrolidin-1-rhinolin,

16. 7-(3-fluoro-phenoxymethyl)-2-methyl-4-pyrrolidin-1-rhinolin,

17. 2-methyl-4-pyrrolidin-1-yl-7-o-tolylacetylene,

18. 2-methyl-4-pyrrolidin-1-yl-7-m-tolylacetylene,

19. 2-methyl-4-pyrrolidin-1-yl-7-p-tolylacetylene,

20. 7-(4-forfinancial)-2-methyl-4-pyrrolidin-1-rhinolin,

21. [3-methoxy-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)phenyl]pyrrolidin-1-ylmethanone,

22. amide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid,

23. 4-azepin-1-yl-7-methoxymethyl-2-methylinosine,

24. 2-methyl-7-(pyridine-4-intoximeter)-4-pyrrolidin-1-rhinolin,

25. 4-azepin-1-yl-7-(2-methoxyethoxymethyl)-2-methylinosine,

26. 7-(4-methoxyphenoxy)-2-methyl-4-pyrrolidin-1-rhinolin,

27. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyrrolidin-1-ylmethanone,

28. (4-tianfeng)amide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid,

29. 2-methyl-4-pyrrolidin-1-yl-7-pyrrolidin-1-iletileri,

30. butylamide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid,

31. 2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)Ben is ontril,

32. 2-chloro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

33. 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-2-cryptomathematical,

34. butyl(2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amine,

35. 2-fluoro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

35A. 4-fluoro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

36. 3-fluoro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

37. 3-chloro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

38. 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)phthalonitrile,

39. 5-bromo-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

40. 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-2-nitrobenzonitrile,

41. 5-fluoro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

42. 2-chloro-6-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

43. 3-fluoro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

44. 2-iodine-6-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

45. 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-3-cryptomathematical,

46. 2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-6-cryptomathematical,

47. 2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-5-cryptomathematical,

48. 3,5-debtor-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

49. 5-methyl-2-(2-methyl-4-pyrrolic the n-1-rhinolin-7-ylethoxy)benzonitrile,

50. 4-bromo-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

51. 4-chloro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

52. 3-fluoro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-4-cryptomathematical,

53. 5-chloro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

54. 4-[2-methyl-4-(4-methylpiperazin-1-yl)quinoline-7-ylethoxy]benzonitrile,

55. 2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-4-cryptomathematical,

56. 4-(2-methyl-4-piperidine-1-rhinolin-7-ylethoxy)benzonitrile,

57. (S)-4-[4-(3-dimethylaminopropan-1-yl)-2-methylinosine-7-ylethoxy]benzonitrile,

58. 4-[2-methyl-4-(4-methyl-[1,4]diazepan-1-yl)quinoline-7-ylethoxy]benzonitrile,

59. (2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol,

60. 4-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

61. 2-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

62. {2-methyl-4-[(S)-2-(tetrahydropyran-2-intoximeter)pyrrolidin-1-yl]quinoline-7-yl}methanol,

63. 4-[(2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]-2-cryptomathematical,

64. (S)-[1-(7-hydroxymethyl-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol,

65. (S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]benzonitrile,

66. (S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]-2-cryptomathematical,

67. (S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-m is tinhinan-7-ylethoxy]-3-cryptomathematical,

68. (S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]phthalonitrile,

69. (S)-2-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]benzonitrile,

70. 4-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-2-cryptomathematical,

71. 4-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-3-cryptomathematical,

72. (S)-[4-(2-methoxypiperidine-1-yl)-2,6-dimethylphenol-7-yl]methanol,

73. (R)-[4-(2-methoxypiperidine-1-yl)-2,6-dimethylphenol-7-yl]methanol,

74. (S)-4-[4-(2-methoxypiperidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile,

75. (R)-4-[4-(2-methoxypiperidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile,

76. (S)-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-yl]methanol,

77. (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile,

78. (4-azepin-1-yl-2,6-dimethylaniline-7-yl)methanol,

79. 4-[(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]-2-cryptomathematical,

80. (S)-1-(7-hydroxymethyl-2,6-dimethylaniline-4-yl)pyrrolidin-3-ol,

81. (2-chloro-6-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol,

82. (4-azepin-1-yl-2-chloro-6-methylinosine-7-yl)methanol,

83. (S)-4-[4-(3-hydroxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile,

84. (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile,

85. (S)-1-[2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)hinali the-4-yl]pyrrolidin-3-ol,

86. (S)-4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline,

87. (6-methoxy-2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol,

88. (6-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol,

89. (8)-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethyl-quinoline-7-yl]methanol,

90. 4-((S)-3-(cyclopropylmethoxy)pyrrolidin-1-yl)-2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline,

91. 4-azepin-1-yl-2-chloro-6-methyl-7-(3-triftormetilfullerenov)quinoline,

92. (S)-4-{[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-ylmethyl]amino}benzonitrile,

93. (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]benzonitrile,

94. (S)-[4-(3-(cyclopropylmethoxy)pyrrolidin-1-yl)-2,6-dimethylphenol-7-yl]methanol,

95. N-[4-azepin-1-yl-6-methyl-7-(3-triftormetilfullerenov)quinoline-2-yl]methylamine,

96. [4-azepin-1-yl-6-methyl-7-(3-triftormetilfullerenov)quinoline-2-yl]dimethylamine,

97. (4-azepin-1-yl-2-dimethylamino-6-methylinosine-7-yl)methanol,

98. (S)-4-[4-(3-(cyclopropylmethoxy)pyrrolidin-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile,

99. 4-(6-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

100. 4-(4-azepin-1-yl-2-dimethylamino-6-methylinosine-7-ylethoxy)benzonitrile,

101. 4-[(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile,

102. (S)-4-{[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylmethyl]amino}benzonitrile,

103. 4-(6-methyl-4-pyrrolidin-1 elhilali the-7-ylethoxy)-2-cryptomathematical,

104. (S)-[4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-yl]methanol,

105. (S)-4-{[4-(2-hydroxyethylpyrrolidine-1-yl)-2,6-dimethylphenol-7-ylmethyl]amino}benzonitrile,

106. 4-[(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)methylamino]benzonitrile,

107. (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-ylethoxy]benzonitrile,

108. (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-ylethoxy]-2-cryptomathematical;

109. (S)-4-{[4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-ylmethyl]amino}-2-cryptomathematical,

110. (S)-4-{[4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-ylmethyl]amino}benzonitrile,

111. methyl ester of 6-bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid and

112. (6-bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol.

Examples of especially preferred compounds of formula I are:

(4-azepin-1-yl-2-methylinosine-7-yl)methanol,

4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

4-(4-azepin-1-yl-2-methylinosine-7-ylethoxy)benzonitrile,

4-[(2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile,

2-methyl-7-(pyridine-4-intoximeter)-4-pyrrolidin-1-rhinolin,

butylamide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid,

2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

2-chloro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

4-(2-methyl-4-pyrrolidin-1-rhinolin-7-elmet the XI)-2-cryptomathematical,

4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)phthalonitrile,

(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol,

4-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile,

4-[(2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]-2-cryptomathematical,

(S)-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-yl]methanol,

(S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethyl-quinoline-7-ylethoxy]benzonitrile,

4-[(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile and

(S)-4-{[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylmethyl]amino}benzonitrile.

The object of the invention are methods of preparing compounds of formula I.

Unless otherwise noted, the below description of the variants of the method of obtaining the substituents and indices have the following values.

Compounds of General formula IA (R1indicates OR4And2denotes CH2) can be obtained in two steps according to scheme 1, using as starting product (4-chlorhydrin-7-yl)methanol derived As:

a) To make the connection And simple (7-henrilevy) ether, the compound a is subjected to interaction with the phenolic derivative, R41-IT (R41denotes aryl, heterocyclyl) in the presence of triphenylphosphine and dialkyldithiocarbamate (for example, diisopropylcarbodiimide) in aprotic solvents is e, such as dichloromethane or toluene at about room temperature (reaction Mitsunobu, see review in Org. React. 42, 1992, s). In another embodiment, the connection process And R41-X (where R41denotes aryl or heterocyclyl and X denotes halogen, preferably F or R42-Y (where R42denotes alkyl or cycloalkyl; Y denotes a leaving group, preferably Br or I) in the presence of a base such as sodium hydride, in a solvent such as N,N-dimethylformamide, at a temperature of 20-100°C. In another embodiment, the conversion of compound a to b is carried out by way of combination reaction with the halide R41-X (where R41denotes aryl or heterocyclyl; X represents halogen, preferably Br or I) in the presence of a base such as sodium hydride or tert-butyl sodium, and systems of palladium catalyst, for example Tris(dibenzylideneacetone)diplegia(0) and 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP), in a solvent such as toluene, at about 50-100° (J. Am. Chem. Soc. 119, 1997, s).

b) a simple Transformation (4-chlorhydrin-7-yl)methyl ester In compound IA is carried out using the appropriate amine at a temperature of 0-200°not necessarily in a sealed tube and/or under microwave irradiation, or by using an excess of amine without solvent or using a 2-20-fold excess is in an acceptable solvent, such as ethanol or 1-methylpyrrolidine-2-he, optionally in the presence of lithium chloride or sodium iodide and pyridine. In the case where R stands for halogen, isomeric 2-aminoquinolinic derived, which can be formed as a by-product, is separated from the desired 4-aminoquinoline, for example by chromatography or crystallization.

According to another variant of the transformation (4-chlorhydrin-7-yl)methanol derived in IA can be done through the IB connection, by modifying the procedure described above the reaction stages (scheme 1).

R30denotes H, alkyl or halogen;

Synthesis of (4-chlorhydrin-7-yl)methanol derived And used as the original 4-chlorhydrin presented in scheme 2.

a) Reaction of a combination of compounds With a metal cyanide such as potassium cyanide, in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), and copper iodide(1) in a solvent such as acetonitrile, at 80° (J. Org. Chem. 63, 1998, s), allows to obtain 4-chlorhydrin-7-carbonitrile D.

b) Alcoholysis of ceanography compound D, preferably in ethanol or methanol solution of hydrogen chloride, at a temperature of from 20°C to the boiling point of the alcohol allows you to get ether 4-chlorhydrin-7-carboxylic key is lots that is,

C) Hydride reduction of compound E with a suitable reagent, preferably hydride diisobutylaluminum, in a solvent such as THF or dichloromethane at a temperature from -78°C to +20°allows to obtain (4-chlorhydrin-7-yl)methanol A.

In another embodiment, the compound a is produced from compound D using a two-stage process in which the cyano compounds D restore using hydride diisobutylaluminum in a solvent such as tetrahydrofuran, at temperatures from -78°0°and received 4-chlorhydrin-7-carbaldehyde (F) is treated with sodium borohydride in a solvent such as methanol, 0-20°C.

According to another variant of the single-stage conversion of connections in the connection E is performed using the carbonylation, i.e. by interaction of the halide or triflate With the corresponding alcohol (Ra-OH, where Rameans (ness.)alkyl, preferably methyl or ethyl), or by using a large excess of alcohol without solvent, or by reaction with a 2-10-fold excess in a suitable solvent, such as N,N-dimethylformamide or methylsulfoxide, in an atmosphere of carbon monoxide at a pressure of 1-100 bar, in the presence of a palladium catalyst system such as palladium(II) acetate and triphenylphosphine or bis(1,3-define phosphino)propane, and bases, such as triethylamine, at a temperature of about 40-80°C.

R30denotes hydrogen, alkyl or halogen; Radenotes methyl or ethyl; X denotes a leaving group, preferably I or OSO2CF3.

Synthesis of quinoline-7-carboxamido General formula IC from 4-chloro-7-gelegenheden presented in figure 3:

a) Interaction of the compounds With the appropriate amines to obtain compound G are similar to the above synthesis of IA of the Century

b) 4-Aminoquinoline-7-carbonitrile derivative of H is obtained from G by reaction combination with a metal cyanide, by analogy with the method described above transformation connection in the connection D.

C) hydrolysis of the compound N, for example, using hydrogen peroxide and potassium hydroxide, preferably in a two-phase mixture of water and dichloromethane and in the presence of a phase transfer catalyst such as tetrabutylammonium bisulfate at a temperature of 0-20°With, allows to obtain a primary amide ID.

g) finally, the transformation ID in the IC are carried out either through interaction with the halide or sulfonate, R42-Y (where R42represents (substituted) alkyl or cycloalkyl, Y denotes a leaving group, preferably Br or I) in the presence of a base such as sodium hydride, in a solvent such as N,N-dime informed, at a temperature of 20-100°or with the help of combination reaction with the halide R41-X (where R41denotes aryl, heterocyclyl, X represents halogen, preferably Br or I) in the presence of a base such as cesium carbonate and a palladium catalyst such as palladium(II) acetate and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), in a solvent such as 1,4-dioxane, at about 50-100° (Org. Lett. 2, 2000, s).

R30denotes hydrogen, alkyl or halogen; X represents a leaving group, preferably I or OSO2CF3.

Synthesis of 4-aminoquinoline-7-carboxamide derivatives IE and (4-aminoquinoline-7-ylmethyl)amines IF carried out according to scheme 4:

a) ester E is transformed into the corresponding amide J by reacting with the appropriate amine or by using a large excess of amine without solvent, or by reaction using a 2-10-fold excess of amine, in a suitable solvent, such as ethanol or N,N-dimethylformamide, at a temperature of from 0°C to boiling point of the amine or solvent.

b) the Interaction of J with the corresponding amines with getting IE perform the same as the above synthesis of the compound IA from compounds Century

in) Making connections in IE connection IF carried out by reaction Gadirov the Oia, for example, using lithium aluminum hydride in a solvent such as tetrahydrofuran, at a temperature of from 0°C to the boiling point of the solvent.

R30denotes hydrogen, alkyl or halogen; Radenotes methyl or ethyl.

Another approach to obtaining the compounds IF (primarily in the case when R5denotes aryl or heterocyclyl) is shown in figure 5:

a) Oxidation of (4-chlorhydrin-7-yl)methanol or with manganese dioxide in a solvent such as dichloromethane or chloroform, at a temperature of from 20°C to the boiling point of the solvent allows to obtain quinoline-7-carbaldehyde derived F.

b) Reductive amination of compounds of F, using the appropriate amine and borohydride reagent such as sodium borohydride or triacetoxyborohydride sodium in the solvent system such as ethanol/acetic acid, ethanol/aqueous hydrochloric acid or 1,2-dichloroethane/acetic acid, 0-20°allows to obtain (4-chlorhydrin-7-yl)methylamine K.

C) Interaction of compounds To the corresponding amines, which allows to obtain the connection IF carried out similarly to the above synthesis of the compound IA from compounds Century

In another embodiment, IF it is possible to synthesize from IB alcohol by oxidation with manganese dioxide (with the according to stage a), followed by reductive amination (according to stage b)

R30denotes hydrogen, alkyl or halogen.

Quinoline derivatives IH (where R20denotes amino, alkoxy) can be obtained from 6-galactopyranose IG derived by reaction cross-combinations using the appropriate amines (R5-NH-R6) or alcohols (R43-HE) in the presence of the catalyst system and the base according to the process described below (scheme 6):

a) In the case when R20denotes alkoxygroup, reaction cross combinations carried out either using the method Ulmann (Ullmann) using a copper catalyst such as copper iodide with the addition of 1,10-phenanthroline or without him, and bases such as tert-butyl sodium or cesium carbonate, using alcohol R43HE as a solvent or in a solvent such as N,N-dimethylformamide, at elevated temperatures (Synthesis 1998, s or Org. Lett. 4, 2002, s), or by using the method of Buchwald (Buchwald) using palladium catalyst, for example Tris(dibenzylideneacetone)diplegia(0) and 2,2'-bis(di-n-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP), in a solvent such as toluene, at a temperature of approximately 50-100° (J. Am. Chem, Soc. 119, 1997, s).

b) In the case when R20oboznachennomu, the transformation is carried out by reaction cross combination Buchwald in the presence of a suitable catalyst system such as palladium(II) acetate and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP)and a base such as tert-butyl sodium, in a solvent such as toluene, at 20-110° (J. Org. Chem. 61, 1996, s).

R20denotes alkoxy or amino; X is Cl, Br or I; R43denotes alkyl.

Quinoline derivatives IK can be obtained from 2-chlorinating derivatives IJ and the corresponding amines according to scheme 7, or by analogy with the synthesis of compounds IA from Within, or through reaction of a combination of Buchwald similar to that described above for the synthesis of compound IH of compound IG.

The esters of the quinoline-7-carboxylic acid of General formula IL can be obtained from compounds G by carbonylation by analogy with the method described above for the synthesis of compounds E compounds from C. Esters IL then can be converted into alcohols by IB hydride recovery by analogy with the method described above for the synthesis of compounds And compound E.

R30denotes hydrogen, alkyl or halogen; Radenotes methyl or ethyl; X denotes a leaving group, preferably I or OSO2CF3.

Getting 4-chlorinolysis pre is represented in schemes 9 and 10 and includes obtaining 3-halogenosilanes or 3-benzyloxyaniline formula L according to the methods known in this field (for an overview see G.Jones, "The chemistry of heterocyclic compounds, volume 32: Quiniolines', part I, published by J.Wiley and Sons, London,1977).

To obtain 4-chlorinolysis formula Cl, 3-halogenation or 3-benzyloxyaniline (L) is subjected to the following transformations depending on the nature of the substituent Rcin situation(2) quinoline:

a) Rcdenotes H: Condensation with dialkyldimethylammonium at 140-150°allows to obtain an intermediate product of M1, which is subjected to cyclization with the removal of one equivalent of alcohol (Ra-OH) at a temperature of approximately 250°in a solvent with a high boiling point, such as Dowtherm a or a simple diphenyl ether. Thus obtained ether 4-chinolin-3-carboxylic acid amyraut (aqueous sodium hydroxide, boiling under reflux) and decarboxylase at high temperature (approximately 250° (C) in a solvent such as Dowtherm®And or simple diphenyl ether, to obtain the 4-quinolone N1 (scheme 9).

b) Rcdenotes alkyl: Condensation with the appropriate β-ketoesters in the presence of n-toluensulfonate acid at the temperature of reflux distilled cyclohexane and destruction in azeotropic conditions of the water that is formed during the reaction allows to obtain an intermediate product M2. Subsequent ring closure with removal of one equivalent the and alcohol (R a-OH) reach by keeping at a temperature of approximately 250°in a solvent with a high boiling point, such as Dowtherm A, obtaining 4-quinolone N1 (scheme 9).

Transformation thus obtained quinolones N1 4-chlorhydrin S1 is carried out, for example, using acid chloride phosphoric acid and optionally in the presence of catalytic amounts of N,N-dimethylformamide at a temperature of about 50°With (scheme 9).

Radenotes methyl or ethyl; Rbdenotes alkyl; Rcdenotes H or alkyl; X represents I, OCH2Ph or Br, preferably I or co2Ph.

To obtain 2,4-dechlorinating formula C2 two equivalent 3-halogenation or 3-benzyloxyaniline (L) condensed with one equivalent of diallylmalonate at high temperature (about 210° (C), and thus there is a gradual destruction of two equivalents of alcohol (Ra-OH). Dianiline intermediate product M3 is subjected to cyclization at a temperature of approximately 250°in molten aluminium chloride and sodium chloride to obtain 4-hydroxy-2-quinolone General formula N2. And, finally, by chlorination using POCl3receive 2,4-dichlorohydrin C2 (scheme 10).

In another embodiment, 2,4-dichlorohydrin C2 can be synthesized in one stage of anilines L, milonov the th acid and POCl 3(J. Chem. Soc., Perkin Trans, 1 1993, s).

Radenotes methyl or ethyl, X represents I, OCH2Ph or Br, preferably I or OCH2Ph.

Quinoline derivative or C3 G1, which are benzyloxy in position(7), can be transformed into the corresponding triflate the quinoline-7-yl C4 and G2, respectively, by a two-step process, presented in figure 11:

a) Otscheplaut fragment simple benzyl ether or C3 G1, for example, or by using a Lewis acid (preferably chloride titanium(IV) in dichloromethane at about 0° (C), or by reduction (hydrogenation in the presence of a suitable catalyst, for example palladium on activated charcoal, in a solvent such as methanol)to give the corresponding quinoline-7-ol.

b) Intermediate products quinoline-7-Ola turn in the appropriate triflate C4 or G2 using a suitable reagent, for example, 3-formeasuring anhydride, in a solvent such as dichloromethane, at a temperature of about -20°C.

C) Interaction of C3 with the corresponding amines with obtaining G1 carried out by analogy with the above described synthesis of IA of the Century

R30denotes hydrogen, alkyl or halogen.

The transformation of compounds of formula I in a pharmaceutically acceptable salt can in order to implement the processing of inorganic acid, for example, halogen acid, such as hydrochloric acid or Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or an organic acid such as acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or n-toluensulfonate acid.

The conversion of compounds of formula I in a pharmaceutically acceptable esters or amides can be done, for example, the processing of acceptable amino or hydroxyl groups present in the molecules of carboxylic acid, such as acetic acid, using a condensing reagent such as hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF) or N,N-dicyclohexylcarbodiimide (DCC) to give the ester of carboxylic acid or carboxylic acid amide.

Preferred intermediates are:

a) ethyl ester of 4-chloro-2-methyl-quinoline-7-carboxylic acid,

b) (4-chloro-2-methylinosine-7-yl)methanol,

b) 4-chloro-2-methylinosine-7-carbaldehyde,

g) 2-methyl-4-pyrrolidin-1-rhinolin-7-carbonitrile,

e) ethyl ether 4-chloro-2,6-dimethyl-quinoline-7-carboxylic acid,

(e) 2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-carbaldehyde;

W) 2,4-dichloro-7-iodine-6-methylinosine,

C) ethyl ester of 2,4-dichloro-6-methylinosine-7-arbonboy acid,

and) (4-chloro-6-methoxy-2-methylinosine-7-yl)methanol,

K) (4-chloro-6-methylinosine-7-yl)methanol,

l) 4-chloro-2,6-dimethylaniline-7-carbaldehyde,

m) 7-benzyloxy-6-bromo-4-chloro-2-methylinosine,

h) 6-bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-silt ether triftormetilfullerenov acid.

Another object of the invention are the above compounds of formula I, intended for use as therapeutically active substances.

The object of the present invention are the above compounds intended for the preparation of drugs for the prevention and treatment of diseases, which are caused by disorders associated with the NPY receptor, primarily for the preparation of drugs for the prevention and treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.

The object of the invention is also pharmaceutical compositions containing the above compound of formula I and a therapeutically inert carrier.

The object of the invention is also the use of the above compounds for the preparation of pharmaceuticals, in particular for the treatment and prevention of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and Aire the Oia.

The next object of the invention are compounds obtained by using one of the described methods.

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

The next object of the invention is a method of treating obesity in a person in need of such treatment, which consists in the introduction of a therapeutically effective amount of the compounds of formula I and a therapeutically effective amount of a lipase inhibitor, where the inhibitor of lipase most preferably represents orlistat. The object of the present invention is also the method, characterized in that the introduction is carried out simultaneously, separately or sequentially.

Another preferred embodiment of the present invention is the use of compounds of formula I for the preparation of a medicine for the treatment and prevention of obesity in a patient who is undergoing a course of treatment with a lipase inhibitor, and a lipase inhibitor most preferably represents orlistat.

The preferred method of obtaining the compounds of formula I pre who sees the implementation of one of the following reactions:

a) compound of the formula Q1 is subjected to interaction in the presence of an amine of the formula Q2 to obtain the compounds of formula Q3

where R1, R2And1and2have the above meanings and R30denotes hydrogen, alkyl or halogen and Y represents chlorine, bromine or iodine;

b) the compound of formula H is subjected to interaction in the presence of hydrogen peroxide to obtain the compounds of formula ID

where R2and1have the meanings indicated in claim 1 of the claims, and R30denotes hydrogen, alkyl or halogen;

C) the compound of formula IE is subjected to interaction in the presence of hydride to obtain the compounds of formula IF

where R2, R5, R6and1have the above meanings and R3denotes hydrogen, alkyl or halogen;

g) the compound of formula IJ is subjected to interaction in the presence of an appropriate amine HNR'R" to obtain the compounds of formula IK

where R1, R2And1and2have the values indicated above and R' and R" independently from each other chosen from the series comprising hydrogen, alkyl and cycloalkyl, or R' and R" together with the N atom to which they are bound, form a 5-to 10-membered heterocyclic ring, the de heterocyclic ring optionally substituted by one or more substituents, independently from each other selected from alkyl and alkoxy, and Y denotes a chlorine, bromine or iodine.

The next object of the invention is described above the compounds of formula I, intended for use as therapeutically active substances.

And another object of the invention are the above compounds intended for the preparation of drugs for the prevention and treatment of diseases, which are caused by disorders associated with the NPY receptor, in particular, for the preparation of drugs for the prevention and treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.

The object of the invention is also a pharmaceutical composition containing the above compound of formula I and a therapeutically inert carrier. Preferably, the composition contains a therapeutically effective amount of a lipase inhibitor. Most preferred is a composition in which as a lipase inhibitor use orlistat.

The object of the invention is also the use of the above compounds for the preparation of pharmaceuticals, in particular for the treatment and prevention of arthritis, cardiovascular diseases, diabetes, renal insufficient the tee and, first of all eating disorders and obesity.

The next object of the invention are compounds obtained by using one of the described methods.

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

The next object of the invention is a method of treating obesity in a person in need of such treatment, which consists in the introduction to the human therapeutically effective amounts of compounds of formula I and a therapeutically effective amount of a lipase inhibitor, where the inhibitor of lipase most preferably represents orlistat. The object of the present invention is also the method, characterized in that the introduction is carried out simultaneously, separately or sequentially.

Another preferred embodiment of the present invention is the use of compounds of formula I for the preparation of a medicine for the treatment and prevention of obesity in a patient who is undergoing a course of treatment with a lipase inhibitor, and a lipase inhibitor most preferably represents orlistat.

Method the analysis

Cloning of cDNA of mouse NPY5 receptor:

Full-size cDNA encoding a murine NPY5 receptor (mNPY5), amplified from brain cDNA of mouse brain using specific primers designed on the basis of the data on published sequences, and DNA polymerase Pfu (firm Stratagene). Amplificatory product was subcloned into the expression vector pcDNA3 mammalian using the restriction sites EcoRI and Xhol. Sequenced positive clones and one clone encoding the published sequence were selected for creation of stable cell clones.

Stable transfection:

Cells of the human embryo kidney line 293 (NEC) was transfectional 10 µg DNA mNPY5 using lipofectamine (reagent company Gibco BRL) according to manufacturer's instructions. 2 days after transfection started breeding geneticin (1 mg/ml), and provided several stable clones. One clone then used to assess the pharmacological characteristics.

Competitive binding radioligand:

Cells of the human embryo kidney line 293 (NEC)expressing recombinant murine NPY5 receptor (mNPY5), was destroyed by three cycles of freezing/thawing in hypotonic Tris buffer (5 mm, pH 7, 4, 1 mm MgCl2), homogenized and centrifuged at 72000×g for 15 min Debris was washed twice with 75 mm the figure-buffer, pH 7.4, containing 25 mm MgCl2and 250 mm sucrose, 0.1 mm by phenylmethylsulfonyl and 0.1 mm 1,10-phenantroline that were resuspendable in the same buffer, and aliquots were stored at -80°C. protein Content was determined by the method of Lowry using as a standard of bovine serum albumin (BSA).

Analysis of competitive binding of radioligand was carried out in 250 μl of 25 mm Hepes buffer (pH 7.4, 2.5 mm CaCl2, 1 mm MgCl2, 1% bovine serum albumin and 0.01% NaN3, which contains 5 μg protein, 100 PM labeled with [125I] peptide YY (PYY) and 10 μl of DMSO, and increasing concentrations of unlabeled test compounds). After incubation for 1 h at 22°bound and free ligand were separated by filtration through glass fiber filters. Nonspecific binding was assessed in the presence of 1 μm unlabeled PYY. Specific binding was defined as the difference between total binding and nonspecific binding. Determine the values of the IC50as the concentration of antagonist, in which there is a 50%displacement of labeled with [125I] neuropeptide y were determined using linear regression analysis after logit/log transformation of the results of the binding.

The table below presents the results obtained using the above analysis of COI is whether the test compounds representative of the compounds, proposed in this invention is:

ConnectionIC50
Example 522 nm
Example 13130 nm

Preferred of the above are compounds whose values IC50is less than 1000 nm; more preferred compounds of the value of the IC50be less than 100 nm. The most preferred compounds of the value of the IC50constitute less than 10 nm. These results were obtained using the above analysis.

The compounds of formula I and their pharmaceutically acceptable salt, solvate, ester can be used as drugs (e.g., in the form of pharmaceutical compositions). The pharmaceutical compositions can be entered inside, for example, orally (for example, as tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasal (e.g., in the form of nasal sprays) or rectally (e.g. in the form of suppositories). The introduction can be carried out parenterally, for example intramuscularly or intravenously (for example, in the form of solutions for injection).

The compounds of formula I and their pharmaceutically acceptable salt, solvate, ester can be treated together with f is rmaceuticals inert inorganic or organic adjuvants to obtain tablets, the coated tablets, dragées and hard gelatin capsules. As such adjuvants for tablets, coated tablets, dragées and hard gelatin capsules can be applied lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc.

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

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

Acceptable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils etc.

Acceptable adjuvants for suppositories are, for example, natural or hydrogenated oils, waxes, fats, semi-solid or liquid polyols etc

In addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, substances that increase the viscosity, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

According to the invention the compounds of formula I and their pharmaceutically when mimie salt, the solvate and esters can be used for prevention and treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity. The dose can vary within wide limits and, of course, depend on the individual modes in each case. As a rule, in the case of oral administration a daily dose of from about 0.1 to 20 mg / kg body weight, preferably about from 0.5 to 4 mg per kg of body weight (for example, about 300 mg per individual), it preferably can be divided into 1-3 individual doses which may, for example, include the same number. However, it should be obvious that, depending on the indications, the upper limit may be increased.

Below the invention is illustrated in the examples, not limiting its scope.

Examples

Example 1

3-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 3-hydroxybenzonitrile and pyrrolidine. The result has been solid yellow, ISP-MS: m/e=to 344.4 ([M+H]+).

Example 2

(2-Methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol:

a) 4-Chloro-2-methylinosine-7-carbonitrile:

Specified in the title compound was obtained from the POM is using a shared method, described in example 226, from 4-chloro-7-iodine-2-methyl-quinoline (EP 497371). The result has been solid white, ISP-MS: m/e=203,0 ([M+H]+).

b) Ethyl ester of 4-chloro-2-methylinosine-7-carboxylic acid

Method a: a Suspension of 4-chloro-2-methylinosine-7-carbonitrile (52 mg, 0.26 mmol) in 8 M ethanol solution of hydrogen chloride (4 ml) was kept at 80°C for 2 hours, After cooling the resulting solution was poured into saturated sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and was evaporated, getting mentioned in the title compound (51 mg, 80%) as a solid white color, ISP-MS: m/e=250,1 ([M+H]+).

Method B: a Mixture containing 4-chloro-7-iodine-2-methylinosine (EP 497371, 20,0 g, 65,9 mmol), palladium(II) acetate (740 mg, 3,30 mmol), triphenylphosphine (864 mg, 3,30 mmol) and triethylamine (20,0 g, 198 mmol) in ethanol (400 ml), was kept in an atmosphere of carbon monoxide at 55°C for 13 hours, After cooling the resulting solution was distributed between saturated aqueous ammonium chloride and ethyl acetate, the organic layer was washed with saturated aqueous solution of ammonium chloride and brine solution, dried (MgSO4) and was evaporated, getting mentioned in the title compound (16,9 g) as a solid yellow color, which was used without further sight of the weave.

in) (4-Chloro-2-methylinosine-7-yl)methanol

Hydride diisobutylaluminum (1 M solution in tetrahydrofuran, 80 ml, 80 mmol) was added dropwise at 0°to a solution of ethyl ester of 4-chloro-2-methylinosine-7-carboxylic acid (4.42 g of 17.7 mmol) in tetrahydrofuran (90 ml), then after stirring for 1 h at 0°the reaction was stopped by gently adding methanol (4.5 ml) and 1 M aqueous solution of tartrate of potassium-sodium (135 ml). A two-phase mixture was stirred for 30 min, then was extracted twice with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, hexane/ethyl acetate, 1:1) has been specified in the header connection (2,62 g, 71%) as a whitish solid, EI-MS: m/e=207,2 (M+).

g) (2-Methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

(4-Chloro-2-methylinosine-7-yl)methanol (750 mg, 3.61 mmol) was boiled under reflux in pyrrolidine (6.42 per g of 90.3 mmol) for 16 h Then a large part of pyrrolidine was removed under reduced pressure, the oily residue was dissolved in toluene was evaporated and the resulting solid is triturated in ethyl acetate, filtered and dried, obtaining mentioned in the title compound (785 mg, 90%) as a solid light brown color, ISP-MS: m/e=243,3 ([M+N]+).

Example 3

(4-Azepin-1-yl-2-methyl-quinoline-7-yl)methanol:

(4-Chloro-methylinosine-7-yl)methanol (example 2C, 1,00 g, 4,82 mmol) kept at 125°in azepane (8,79 g of 90.3 mmol) for 18 hours After cooling, the reaction mixture was distributed between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography on SiO2(ethyl acetate, then CH2Cl2/MeOH/NH4OH, 95:5:0.1) has been specified in the title compound (320 mg, 25%) as a solid light yellow color, ISP-MS: m/e=271,4 ([M+H]+).

Example 4

3-(4-Azepin-1-yl-2-methylinosine-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 3-hydroxybenzonitrile and azepane. The result has been solid light yellow color, ISP-MS: m/e=372.3 ([M+H]+).

Example 5

4-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 4-perbenzoate. The result has been solid white, ISP-MS: m/e=344,3 ([M+H]+).

Example 6

4-(4-Azepin-1-yl-2-methylinosine-7-ylethoxy)benzonitrile:

Sodium hydride (55-65%dispersion in mineral oil, 22 mg, 0.55 mmol) was added to the mixture, with the holding (4-azepin-1-yl-2-methylinosine-7-yl-methanol (example 3, 120 mg, 0.44 mmol) and 4-perbenzoate (54 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 ml). After incubation for 2 h at 50° the reaction mixture was distributed between saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2CH2Cl2/MeOH, 95:5) has been specified in the title compound (144 mg, 87%) as a solid light yellow color, ISP-MS: m/e=372,3 ([M+H]+).

Example 7

2-Methyl-4-pyrrolidin-1-yl-7-(3-triftormetilfullerenov)quinoline:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 3-triptoreline and pyrrolidine. The result has been a solid light brown color, ISP-MS: m/e=387,3 ([M+H]+).

Example 8

2-Metal-4-pyrrolidin-1-yl-7-(4-triftormetilfullerenov)quinoline:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 4-triptoreline and pyrrolidine. The result has been a solid light brown color, ISP-MS: m/e=387,3 ([M+H]+).

Example 9

(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)-(3-triptoreline)Amin:

Specified in the header of connection produces and using General method, described in example 136, from 4-chloro-2-methylinosine-7-carbaldehyde (example 13A), 3-triptorelin and pyrrolidine. The result has been solid white, ISP-MS: m/e=386,3 ([M+H]+).

Example 10

2-Methyl-7-phenoxymethyl-4-pyrrolidin-1-rhinolin:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), phenol and pyrrolidine. The result has been a solid light brown color, ISP-MS: m/e=to 344.4 ([M+H]+).

Example 11

4-Azepin-1-yl-2-methyl-7-(3-triftormetilfullerenov)quinoline:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 3-triptoreline and azepane. The result has been a whitish solid, ISP-MS: m/e=of 415.3 ([M+H]+).

Example 12

7-(3-Methoxyphenoxy)-2-methyl-4-pyrrolidin-1-rhinolin:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 3-methoxyphenol and pyrrolidine. The result has been solid yellow, ISP-MS: m/e=349,4 ([M+H]+).

Example 13

4-[(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile:

a) 4-Chloro-2-methylinosine-7-carbaldehyde:

Method a: a Mixture, the content is relevant (4-chloro-2-methylinosine-7-yl)methanol (example 2C, 500 mg, is 2.41 mmol) and manganese dioxide (2,09 g, 24,1 mmol)were heated under reflux in dichloromethane (14 ml) for 3.5 hours After cooling nerastvorim product was removed by filtration through a bed of dicalite and the filtrate was evaporated, getting mentioned in the title compound (403 mg, 81%) as a solid white color, ISP-MS: m/e=206,1 ([M+H]+).

Method B: the Hydride diisobutylaluminum (1 M solution in dichloromethane, to 0.60 ml of 0.60 mmol) was added dropwise to a solution of 4-chloro-2-methylinosine-7-carbonitrile (example 2A, 100 mg, 0.49 mmol) in dichloromethane (2 ml) at -20°C. After 2 h the temperature was allowed to reach 0°With, then after 2 h the reaction was stopped by adding 1 M aqueous solution of tartrate of potassium-sodium. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, hexane/ethyl acetate, 4:1, then dichloromethane/methanol, 19:1) has been specified in the title compound (40 mg, 39%).

b) 4-[(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile:

Borohydride sodium (101 mg, 2.68 mmol) was added dropwise at 0°to a mixture containing 4-chloro-2-methylinosine-7-carbaldehyde (101 mg, 0.49 mmol), 3-triptorelin (72 mg, 0.45 mmol), sodium sulfate (70 mg, 0.49 mmol) and sodium acetate (121 mg, 1.48 mmol) in ethanol (2 ml) and acetic acid (1 ml). The reaction mixture was stirred for 2 h at 0°and 1 is at room temperature (RT), then was poured into 1 M aqueous sodium hydroxide solution and was extracted with simple ether. The organic layer was washed with brine, dried (MgSO4) and was evaporated. The resulting product (160 mg) was dissolved in pyrrolidine (0,97 ml, 13.7 mmol) and kept for 16 h at 80°C. After cooling, the solution was distributed between ethyl acetate and 1 M aqueous carbonate buffer (pH of 10.3). The organic layer was washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, hexane/ethyl acetate, 1:1, then dichloromethane/methanol, 19:1) were receiving solid, which is triturated in a simple ether, filtered and dried, obtaining mentioned in the title compound (58 mg, 33%) as a solid white color, ISP-MS: m/e=343,3 ([M+H]+).

Example 14

7-(2-Methoxyphenoxy)-2-methyl-4-pyrrolidin-1-rhinosinusal:

Diisopropylethylamine (97 mg, 0.48 mol) was added dropwise at RT to a solution containing (4-chloro-2-methylinosine-7-yl)methanol (example 2C, 100 mg, 0.48 mmol), triphenylphosphine (126 mg, 0.48 mmol), 2-methoxyphenol (60 mg, 0.48 mmol) in dichloromethane (2.5 ml). After shaking for 24 h at RT the solvent is evaporated and the residue was dissolved in pyrrolidine (1,37 g, 19.2 mmol) and was shaken for 23 h at 80°C. After cooling, the reaction mixture was distributed between saturated aqueous ammonium chloride and dichlo is methane, the organic layer was washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 19:1) has received a yellow solid, which was dissolved in ethanol and was treated with 20%ethanol solution of oxalic acid. The precipitate was collected by filtration and dried, obtaining mentioned in the title compound (90 mg, 43%) in the form of a whitish solid, ISP-MS: m/e=349,4 ([M+H-C2H2O4]+).

Example 15

7-(2-Forfinancial)-2-methyl-4-pyrrolidin-1-rhinolin:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 2-terfenol and pyrrolidine. The result has been a solid light brown color, ISP-MS: m/e=337,3 ([M+H]+).

Example 16

7-(3-Forfinancial)-2-methyl-4-pyrrolidin-1-rhinosinusal:

Specified in the title compound was obtained using the General method described in example 14 from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 3-terfenol and pyrrolidine. The result has been a whitish solid, ISP-MS: m/e=337,3 ([M+H-C2H2O4]+).

Example 17

2-Methyl-4-pyrrolidin-1-yl-7-o-tolylacetylene

Specified in the title compound was obtained using the General method described in example 14 from (4-chloro-2-METHYLPHENOL the-7-yl)methanol (example 2C), 2-METHYLPHENOL and pyrrolidine. The result has been a whitish solid, ISP-MS: m/e=to 333.3 ([M+H-C2H2About4]+).

Example 18

2-Methyl-4-pyrrolidin-1-yl-7-m-tolylacetylene:

Specified in the title compound was obtained using the General method described in example 14 from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 3-METHYLPHENOL and pyrrolidine. The result has been a whitish solid, ISP-MS: m/e=333,4 ([M+H-C2H2O4]+).

Example 19

2-Methyl-4-pyrrolidin-1-yl-7-p-tolylacetylene:

Specified in the title compound was obtained using the General method described in example 14 from (4-chloro-2-methyl-quinoline-7-yl)methanol (example 2C), 4-METHYLPHENOL and pyrrolidine. The result has been a whitish solid, ISP-MS: m/e=to 333.3 ([M+H-C2H2O4]+).

Example 20

7-(4-Forfinancial)-2-methyl-4-pyrrolidin-1-rhinolin:

Diisopropylethylamine (97 mg, 0.48 mmol) was added dropwise at RT to a solution containing (4-chloro-2-methylinosine-7-yl)methanol (example 2C, 100 mg, 0.48 mmol), triphenylphosphine (126 mg, 0.48 mmol) and 4-terfenol (54 mg, 0.54 mmol) in dichloromethane (2.5 ml). After shaking for 24 h at RT the solvent is evaporated and the residue was dissolved in pyrrolidine (1,37 g, 19.2 mmol) and was shaken for 23 h at 80°C. After cooling, the reaction is ionic mixture was distributed between saturated aqueous ammonium chloride and dichloromethane, the organic layer was washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 19:1) has been specified in the title compound (66 mg, 41%) in the form of a whitish solid, ISP-MS: m/e=337 ([M+H]+).

Example 21

[3-Methoxy-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)phenyl]pyrrolidin-1-yl-methanon:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 4-hydroxy-3-methoxybenzonitrile and pyrrolidine. The result has been a solid light brown color, ISP-MS: m/e=446,3 ([M+H]+).

Example 22

Amide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid:

a) 7-Iodine-2-methyl-4-pyrrolidin-1-rhinolin

A suspension of 4-chloro-7-iodine-2-methylinosine (EP 497371, 2.00 g, 6,59 mmol) in ethanol (20 ml) was treated sequentially with pyrrolidine (1.28 g, 18.0 mmol), pyridine (0.2 ml) and potassium iodide (50 mg, 0.30 mmol) and the resulting mixture was boiled under reflux for 24 hours After concentration in vacume the residue was dissolved in water (50 ml) and podslushivaet to pH 12 by adding a 2 M aqueous solution of sodium hydroxide. The precipitate was collected by filtration, washed with water (20 ml) and simple ether (20 ml) and dried, obtaining specified in the header connection (1,95 g, 87%) as a whitish solid, tPL/sub> 99-102°C.

b) 2-Methyl-4-pyrrolidin-1-rhinolin-7-carbonitrile (72-3186)

The suspension containing 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin (1.50 g, 4,43 mmol), potassium cyanide (578 mg, 8,87 mmol),

tetrakis(triphenylphosphine)palladium(0) (256 mg, 0.22 mmol) and copper iodide (85 mg, 0.44 mmol) in acetonitrile (10 ml)was boiled under reflux for 90 minutes After cooling, the mixture was diluted with ethyl acetate, filtered and the filtrate was washed with brine, dried (Na2SO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 19:1) has been specified in the header connection (791 mg, 75%) as a solid light brown color, ISP-MS: m/e=238,3 ([M+H]+).

C) Amide-2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid

A solution of 2-methyl-4-pyrrolidin-1-rhinolin-7-carbonitrile (100 mg, 0.42 mol) in dichloromethane (1 ml) was treated at 0°With 30%aqueous hydrogen peroxide solution (0.5 ml), tetrabutylammonium bisulfate (29 mg, 84 μmol) and 20%aqueous solution of sodium hydroxide (0.5 ml). After removing the ice bath two-phase mixture was stirred at RT for 2 h, then the organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 9:1) has been specified in the title compound (65 mg, 60%) as a solid light brown color, ISP-MS m/e=256, ([M+H] +).

Example 23

4-Azepin-1-yl-7-methoxymethyl-2-methylinosine:

Specified in the title compound was obtained using the General method described in example 25 (4-azepin-1-yl-2-methylinosine-7-yl)methanol (example 3) and iodomethane. The result has been solid light yellow color, ISP-MS: m/e=285,3 ([M+H]+).

Example 24

2-Methyl-7-(pyridine-4-intoximeter)-4-pyrrolidin-1-rhinolin:

Sodium hydride (55-65%dispersion in mineral oil, 40 mg, 1.0 mmol) was added to a mixture containing (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2, 100 mg, 0.41 mmol) and the hydrochloride of 4-chloropyridine (62 mg, 0.41 mmol)and the mixture was stirred at 90°C for 18 hours and Then added a second portion of sodium hydride (40 mg), and hydrochloride of 4-chloropyridine (62 mg) and stirring at 90°continued for 24 hours After cooling, the reaction mixture was distributed between 1 M aqueous solution of sodium carbonate and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 9:1) has been specified in the title compound (32 mg, 24%) as a solid yellow color, ISP-MS: m/e=320,4 ([M+H]+).

Example 25

4-Azepin-1-yl-7-(2-methoxyethoxymethyl)-2-methylinosine:

Sodium hydride (55-65%dispersion in mineral oil, 10 mg, 0.25 mmol) was added to the solution, terashima (4-azepin-1-yl-2-methylinosine-7-yl)methanol (example 3, 50 mg, 0,19 mmol) and 1-bromo-2-methoxyethane (15 mg, 0,19 mmol) in N,N-dimethylformamide (2 ml). After incubation for 22 hours at 50°was added another portion of sodium hydride (10 mg) and 1-bromo-2-methoxyethane (15 mg) and stirring continued for 16 h Then the reaction mixture was distributed between 1 M aqueous solution of sodium carbonate and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 9:1) has been specified in the title compound (20 mg, 33%) as a yellow oil, ISP-MS: m/e=329,4 ([M+H]+).

Example 26

7-(4-Methoxyphenoxy)-2-metal-4-pyrrolidin-1-rhinolin:

Specified in the title compound was obtained using the General method described in example 20, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C), 4-methoxyphenol and pyrrolidine. The result has been a whitish solid, ISP-MS: m/e=349,5 ([M+H]+).

Example 27

(2-Methyl-4-pyrrolidin-1-rhinolin-7-yl)pyrrolidin-1-ylmethanone:

(4-Chloro-2-methylinosine-7-yl)methanol (example 2, 200 mg, 0.80 mmol) was kept in pyrrolidine (2 ml) at 70°within 48 hours After cooling, the reaction mixture was distributed between saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, dried (MgSO4) and was evaporated. Chromatography (SiO2CH2Cl 2/Meon, 19:1) has been specified in the title compound (134 mg, 54%) as a solid light yellow color, ISP-MS: m/e=310,3 ([M+H]+).

Example 28

(4-Tianfeng)amide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid:

The suspension containing amide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid (50 mg, 0.20 mmol), 4-idententical (45 mg, 0.20 mmol), Xanthos (6,8 mg, 12 μmol), cesium carbonate (89 mg, 0.27 mmol) and palladium (II) acetate (1.8 mg, 8 μmol) in 1,4-dioxane (0.5 ml), was stirred in argon atmosphere at 50°C for 22 h, then the reaction mixture was distributed between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 19:1) has been specified in the title compound (18 mg, 26%) as a solid light yellow color, ISP-MS: m/e=357,3 ([M+H]+).

Example 29

2-Methyl-4-pyrrolidin-1-yl-7-pyrrolidin-1-iletileri:

Alumoweld lithium (20 mg, 0.52 mmol) was added to a solution of (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyrrolidin-1 ylmethanone (example 27, 80 mg, 0.26 mmol) in tetrahydrofuran (1 ml) and the reaction mixture was stirred at room temperature for 3 h, then was added 1 M aqueous solution of tartrate of potassium-sodium (10 ml) and ethyl acetate (10 ml). After 15 min organic the ski layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 9:1) has been specified in the title compound (31 mg, 41%) in the form of a whitish solid, ISP-MS: m/e=337,3 ([M+H]+).

Example 30

Butylamide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid:

(4-Chloro-2-methylinosine-7-yl)methanol (example 2, 200 mg, 0.80 mmol) was boiled under reflux in butylamine (2 ml) for 6 hours After cooling, the reaction mixture was distributed between saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, dried (MgSO4), and was evaporated. The residue was chromatographically (SiO2CH2Cl2/MeOH, 19:1)to give yellow oil, which was kept in pyrrolidine (2 ml) at 70°C for 16 hours After cooling, the reaction mixture was distributed between saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 19:1) has been specified in the title compound (108 mg, 43%) as a solid white color, ISP-MS: m/e=312,3 ([M+H]+).

Example 31

2-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-ilhi the Olin-7-yl)methanol (example 2) and 2-perbenzoate. The result has been solid white, ISP-MS: m/e=to 344.4 ([M+H]+).

Example 32

2-Chloro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2-chloro-4-perbenzoate. The result has been solid light yellow color, ISP-MS: m/e=378,3 ([M+H]+).

Example 33

4-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-2-cryptomathematical:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 4-fluoro-2-triftormetilfosfinov. The result has been solid white, ISP-MS: m/e=412,3 ([M+H]+).

Example 34

Butyl(2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)Amin:

Specified in the title compound was obtained using the General method described in example 29, from butylamide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid (example 30). The result has received a yellow oil, ISP-MS: m/e=298,4 ([M+H]+).

Example 35

A mixture of 2-fluoro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile and 4-fluoro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile (1:1):

Specified in the title compound was obtained using General IU the ode, described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2,4-difterential. The result has been solid yellow, ISP-MS: m/e=362,2 ([M+H]+). The compounds can be separated using conventional methods such as chromatography.

Example 36

3-Fluoro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 3,4-difterential. The result has been solid light yellow color, ISP-MS: m/e=362,3 ([M+H]+).

Example 37

3-Chloro-4-(2-metal-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 3-chloro-4-perbenzoate. The result has been solid light yellow color, ISP-MS: m/e=378,3 ([M+H]+).

Example 38

4-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)phthalonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 4-portalonline. The result has been solid light yellow color, ISP-MS: m/e=369,3 ([M+H]+ ).

Example 39

5-Bromo-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 5-bromo-2-perbenzoate. The result has been solid light yellow color, ISP-MS: m/e=422,3, 424,3 ([M+H]+).

Example 40

4-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-2-nitrobenzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 4-fluoro-2-nitrobenzonitrile. The result has been solid yellow, ISP-MS: m/e=389,3 ([M+H]+).

Example 41

5-fluoro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2,5-difterential. The result has been solid light yellow color, ISP-MS: m/e=362,3 ([M+H]+).

Example 42

2-Chloro-6-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2-chloro-6-perbenzoate. In the result of which was alocale solid light yellow color, ISP-MS: m/e=378,4 ([M+H]+).

Example 43

3-fluoro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2,3-difterential. The result has been solid light yellow color, ISP-MS: m/e=362,3 ([M+H]+).

Example 44

2-Iodine-6-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2-fluoro-6-idententical. The result has been solid light yellow color, ISP-MS: m/e=470,2 ([M+H]+).

Example 45

4-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-3-cryptomathematical:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 4-fluoro-3-triftormetilfosfinov. The result has been solid light yellow color, ISP-MS: m/e=412,4 ([M+H]+).

Example 46

2-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-6-cryptomathematical:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (PR which measures 2) and 2-fluoro-6-triftormetilfosfinov. The result has been solid light yellow color, ISP-MS: m/e=412,4 ([M+H]+).

Example 47

2-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ilmajoki)-5-cryptomathematical:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2-fluoro-5-triftormetilfosfinov. The result has been solid light yellow color, ISP-MS: m/e=412,4 ([M+H]+).

Example 48

3,5-Debtor-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2,3,5-tripersonal. The result has been solid light yellow color, ISP-MS: m/e=380,4 ([M+H]+).

Example 49

5-Methyl-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2-fluoro-5-methylbenzonitrile. The result has been solid light yellow color, ISP-MS: m/e=358,4 ([M+H]+).

Example 50

4-Bromo-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using General method izlojeno the example 6, from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 4-bromo-2-perbenzoate. The result has been solid light yellow color, ISP-MS: m/e=422,4, 424,4 ([M+H]+).

Example 51

4-Chloro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 4-chloro-2-perbenzoate. The result has been solid light yellow color, ISP-MS: m/e=378,4 ([M+H]+).

Example 52

3-fluoro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-4-cryptomathematical:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2,3-debtor-4-triftormetilfosfinov. The result has been solid light yellow color, ISP-MS: m/e=430,6 ([M+H]+).

Example 53

5-Chloro-2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 5-chloro-2-perbenzoate. The result has been solid light yellow color, ISP-MS: m/e=378,4 ([M+H]+).

Example 54

4-[2-Methyl-4-(4-methylpiperazin-1-yl)quinoline-7-ylethoxy]Ben is ontril:

a) 4-(4-Chloro-2-methylinosine-7-ylethoxy)benzonitrile

Sodium hydride (55-65%dispersion in mineral oil, 220 mg of 5.50 mmol) was added to a solution containing (4-chloro-2-methyl-quinoline-7-yl)methanol (example 2C, 1.10 g, and 5.30 mmol) and 4-perbenzoate (642 mg, and 5.30 mmol) in N,N-dimethylformamide (20 ml)and the resulting mixture was stirred at 50°C for 3 hours After cooling, the mixture was distributed between saturated aqueous ammonium chloride and dichloromethane, the organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 19:1) has been specified in the header connection (1,28 g, 78%) as a solid yellow color, ISP-MS: m/e=309,3 ([M+H]+).

b) 4-[2-Methyl-4-(4-methylpiperazin-1-yl)quinoline-7-ylethoxy]benzonitrile

A solution containing 4-(4-chloro-2-methylinosine-7-ylethoxy)benzonitrile (100 mg, 0.32 mmol) and 1-methylpiperazine (81 mg, 0.81 mmol) in 1-methylpyrrolidine-2-Ohe (1.5 ml), was stirred at 100°within 24 hours After cooling, the reaction mixture was distributed between saturated aqueous sodium bicarbonate and dichloromethane, the organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 19:1) has been specified in the title compound (80 mg, 66%) as oil is light yellow in color, ISP-C: m/e=373,5 ([M+H] +).

Example 55

2-(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-4-cryptomathematical:

Specified in the title compound was obtained using the General method described in example 6 from (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 2) and 2-fluoro-4-triftormetilfosfinov. The result has been solid white, ISP-MS: m/e=412,4 ([M+H]+).

Example 56

4-(2-Methyl-4-piperidine-1-rhinolin-7-ylethoxy)benzonitrile:

A solution of 4-(4-chloro-2-methylinosine-7-ylethoxy)benzonitrile (example 54A, 100 mg, 0.32 mmol) in piperidine (1 ml) was kept at 100°for 21h. After cooling, the reaction mixture was distributed between saturated aqueous sodium bicarbonate and dichloromethane, the organic layer was separated, washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, dichloromethane/methanol, 19:1) has been specified in the title compound (40 mg, 32%) as a resin, light yellow, ISP-MS: m/e=358,4 ([M+H]+).

Example 57

(S)-4-[4-(3-dimethylaminopropan-1-yl)-2-methylinosine-7-ylethoxy]benzonitrile:

Specified in the title compound was obtained using the General method described in example 54b, from 4-(4-chloro-2-methylinosine-7-ylethoxy)benzonitrile (example 54A) and (S)-3-(dimethylamino)pyrrolidine. The result has been solid brown, ISP-MS: m/e=387,4 ([M+H]+.

Example 58

4-[2-Methyl-4-(4-methyl-[1,4]diazepan-1-yl)quinoline-7-ylethoxy]benzonitrile:

Specified in the title compound was obtained using the General method described in example 54b, from 4-(4-chloro-2-methylinosine-7-ylethoxy)benzonitrile (example 54A) and 1-methylhomopiperazine. The result has been solid yellow, ISP-MS: m/e=387,4 ([M+H]+).

Example 59

(2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol:

a) 4-Chloro-7-iodine-2,6-dimethylphenol

The suspension containing 3-iodine-4-methylaniline (50.0 g, 215 mmol) and monohydrate toluene-4-sulfonic acid (430 mg, of 2.15 mmol), was heated under reflux for 2 h in cyclohexane (100 ml), allowing produced water to be collected using traps Dean-stark (Dean-Stark), then after cooling nerastvorim product was removed by filtration and the filtrate was evaporated. The residue was dissolved in Dowtherm®A (25 ml) and added dropwise to a hot (temperature approximately 250° (C) Dowtherm®And, After 15 min the reaction mixture was allowed to cool to room temperature, then was added heptane (150 ml) and the precipitate was collected by filtration. This product is triturated in ethyl acetate, obtaining a mixture (1:1) 7-iodine-2,6-methyl-1H-quinoline-4-it 5-iodine-2,6-dimethyl-1H-quinoline-4-it (46.4 g). Chlorination of these isomeric quinolones was performed using the General method outlined in example 88 was Carried out perakis is alizatio mixture of products (4-chloro-7-iodine-2,6-dimethylaniline and 4-chloro-5-iodine-2,6-dimethylaniline) in hexane/ethyl acetate, 9:1 (150 ml), receiving specified in the header of the connection (of 7.55 g, 11%) as a solid light brown color, ISP-MS: m/e=318,1 ([M+H]+).

b) Ethyl ester of 4-chloro-2,6-dimethylaniline-7-carboxylic acid

Specified in the title compound was obtained using the General method described in example 26 (method B) from 4-chloro-7-iodine-2,6-dimethylaniline. The result has been solid white, ISP-MS: m/e=264,3 ([M+H]+).

in) (4-Chloro-2,6-dimethylaniline-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 2B, ethyl ester 4-chloro-2,6-dimethylaniline-7-carboxylic acid. The result has been solid white, ISP-MS: m/e=222, ([M+H]+).

g) (2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 2 g of (4-chloro-2,6-dimethylaniline-7-yl)methanol and pyrrolidine. The result has been solid white, ISP-MS: m/e=257,2 ([M+H]+).

Example 60

4-(2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 59) and 4-perbenzoate. The result has been solid white, ISP-MS: m/e=358,3 ([M+H]+).

Example 61

2-(2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile:

Specified in the title compound was obtained using the General method described in example 6 from (2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 59) and 2-perbenzoate. The result has received a yellow foam, ISP-MS: m/e=358,3 ([M+H]+).

Example 62

{2-Methyl-4-[(S)-2-(tetrahydropyran-2-intoximeter)pyrrolidin-1-yl]quinoline-7-yl} methanol:

a) Benzyl ester of (S)-2-(tetrahydropyran-2-intoximeter)pyrrolidin-l-carboxylic acid

A solution of L-prolinol (1,00 g, 4,94 mmol) in N,N-dimethylformamide (5 ml) was cooled to 0°and were treated with sodium bicarbonate (831 mg, 9,87 mmol) and benzylchloride (843 mg, 4,94 mmol). After removing the ice bath, the reaction mixture was stirred for 1 h at RT, then poured on ice and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and was evaporated. The residue was dissolved in dichloromethane (5 ml)was treated with 3,4-dihydro-2H-Piran (1,25 g of 14.8 mmol) and toluene-4-sulfonate pyridinium (1,37 g, 5.43 mmol) and was stirred for 48 h at RT, then evaporated. The residue was distributed between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2, hexane/ethyl acetate, 3:1) has been specified in the title compound (451 mg, 29%) as a colourless liquid, ISP-MS: m/e=320,4 ([M+H]+).

b) (S)-2-(Tetrahydropyran-2-intoximeter)pyrrolidin

Benzyl ether of (S)-2-(tetrahydropyran-2-intoximeter)pyrrolidin-1-carboxylic acid (445 mg, of 1.39 mmol) was dissolved in ethanol (9 ml) and was first made at atmospheric pressure and room temperature in the presence of 10%palladium on charcoal (10 mg). After 16 h the reaction mixture was passed through a filter and evaporated, getting mentioned in the title compound (255 mg, 99%), liquid black, ISP-MS: m/e=186,3 ([M+H]+), which was used without further purification. C) {2-Methyl-4-[(S)-2-(tetrahydropyran-2-intoximeter)pyrrolidin-1-yl]quinoline-7-yl}methanol

Specified in the title compound was obtained using the General method described in example 54b, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C) and (S)-2-(tetrahydropyran-2-intoximeter)pyrrolidine. The result obtained resin orange, ISP-MS: m/e=357,3 ([M+H]+).

Example 63

4-[(2-Methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]-2-cryptomathematical:

a) 4-[(4-Chloro-2-methylinosine-7-ylmethyl)amino]-2-cryptomathematical (RO 4461847-000-001)

To a solution of 4-chloro-2-methylinosine-7-carbaldehyde (example 13A, 180 mg, 0,875 mmol) in ethanol (3 ml) was added 4-amino-2-cryptomathematical (163 mg, 0,875 mmol), 25%aqueous solution of hydrochloric acid (1.5 ml) and borohydride sodium (207 mg, the 5.25 mmol). Reaction the second mixture was stirred for 16 h at RT, then was distributed between ethyl acetate and 1 M aqueous sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2, hexane/ethyl acetate, 1:1) has been specified in the title compound (123 mg, 37%) in the form of a whitish solid, ISP-MS: m/e=376.3 on ([M+H]+).

b) 4-[(2-Methyl-4-pyrrolidin-1-rhinolin-7-inmetal)amino]-2-cryptomathematical

Specified in the title compound was obtained using the General method outlined in example 56, 4-[(4-chloro-2-methylinosine-7-ylmethyl)amino]-2-triftormetilfosfinov and pyrrolidine. The result has been a white foam, ISP-MS: m/e=411,3 ([M+H]+).

Example 64

(S)-[1-(7-Hydroxymethyl-2-methylinosine-4-Y1)pyrrolidin-2-Y1]methanol

The solution containing {2-methyl-4-[(S)-2-(tetrahydropyran-2-intoximeter)pyrrolidin-1-yl]quinoline-7-yl}methanol (50 mg, 0.14 mmol) and toluene-4-sulfonate pyridinium (39 mg, 0.15 mmol) in ethanol (1 ml)was stirred at 55°C for 72 h, then was distributed between ethyl acetate and 1 M aqueous sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2CH2Cl2/MeOH/NH4OH, 90:10:0.1) has been specified in the title compound (25 mg, 65%) as a yellow resin, ISP-MS: m/e=273,3 ([M+H]+).

the example 65

(S)-4-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 54b, from 4-(4-chloro-2-methylinosine-7-ylethoxy)benzonitrile (example 54A) and L-prolinol. The result has been the foam light yellow ISP-MS: m/e=374,5 ([M+H]+).

Example 66

(S)-4-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]-2-cryptomathematical

a) 4-(4-Chloro-2-methylinosine-7-ylethoxy)-2-cryptomathematical

Specified in the title compound was obtained using the General method described in example 54A, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C) and 4-fluoro-2-triftormetilfosfinov. The result has been a whitish solid, ISP-MS: m/e=377,3 ([M+H]+).

b) (S)-4-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]-2-cryptomathematical

Specified in the title compound was obtained using the General method described in example 54b, from 4-(4-chloro-2-methylinosine-7-ylethoxy)-2-triftormetilfosfinov and L-prolinol. The result has been solid light yellow color, ISP-MS: m/e=442,4 ([M+H]+).

Example 67

(S)-4-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]-3-cryptomathematical

a) 4-(4-Chloro-2-methylinosine-7-ylethoxy)-3-cryptomathematical

Specified in reception is e compound was obtained using General method, described in example 54A, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C) and 4-fluoro-3-triftormetilfosfinov. The result has been a whitish solid, ISP-MS: m/e=377,3 ([M+H]+).

b) (S)-4-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]-3-cryptomathematical

Specified in the title compound was obtained using the General method described in example 54b, from 4-(4-chloro-2-methylinosine-7-ylethoxy)-3-triftormetilfosfinov and L-prolinol. The result has been solid light yellow color, ISP-MS: m/e=442,4 ([M+H]+).

Example 68

(S)-4-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]phthalonitrile

a) 4-(4-Chloro-2-methylinosine-7-ylethoxy)phthalonitrile

Specified in the title compound was obtained using the General method described in example 54A, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C) and 4-portalonline. The result has been a white foam, ISP-MS: m/e=334,2 ([M+H]+).

b) (S)-4-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]phthalonitrile

Specified in the title compound was obtained using the General method described in example 54b, from 4-(4-chloro-2-methylinosine-7-ylethoxy)phthalonitrile and L-prolinol. The result has been solid white, ISP-MS: m/e=399,5 ([M+H]+).

Example 69

(S)-2-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl is ethoxy]benzonitrile

a) 2-(4-Chloro-2-methylinosine-7-ylethoxy)benzonitrile

Specified in the title compound was obtained using the General method described in example 54A, from (4-chloro-2-methylinosine-7-yl)methanol (example 2C) and 2-perbenzoate. The result has been solid light yellow color, ISP-MS: m/e=309,2 ([M+H]+).

b) (S)-2-[4-(2-Hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 54b, from 2-(4-chloro-2-methylinosine-7-ylethoxy)benzonitrile and L-prolinol. The result has been solid light yellow color, ISP-MS: m/e=374,4 ([M+H]+).

Example 70

4-(2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-2-cryptomathematical

Specified in the title compound was obtained using the General method described in example 6 from (2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 59) and 4-fluoro-2-triftormetilfosfinov. The result has been solid white, ISP-MS: m/e=426,4 ([M+H]+).

Example 71

4-(2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-3-cryptomathematical

Specified in the title compound was obtained using the General method described in example 6 from (2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example V) and 4-fluoro-3-triftormetilfosfinov. The result has been solid emesto light yellow color, ISP-MS: m/e=426,4 ([M+H]+).

Example 72

(S)-[4-(2-Methoxypiperidine-1-yl)-2,6-dimethylphenol-7-yl]methanol

Specified in the title compound was obtained using the General method described in example 54b, from (4-chloro-2,6-dimethylaniline-7-yl)methanol (example V) and (S)-2-(methoxymethyl)pyrrolidine. The result has been a white foam, ISP-MS: m/e=301,4 ([M+H]+).

Example 73

(R)-[4-(2-Methoxypiperidine-1-yl)-2,6-dimethylphenol-7-yl]methanol

Specified in the title compound was obtained using the General method described in example 54b, from (4-chloro-2,6-dimethylaniline-7-yl)methanol (example V) and (R)-2-(methoxymethyl)pyrrolidine. The result has been a white foam, ISP-MS: m/e=301,3 ([M+H]+).

Example 74

Hydrochloride (S)-4-[4-(2-methoxypiperidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 6, from (S)-[4-(2-methoxypiperidine-1-yl)-2,6-dimethylphenol-7-yl]methanol (example 72) and 4-perbenzoate and was isolated as hydrochloride. The result has been solid white, ISP-MS: m/e=402,5 ([M-Cl]+).

Example 75

Hydrochloride (R)-4-[4-(2-methoxypiperidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 6, from (R)-[4-(2-methox is methylpyrrolidine-1-yl)-2,6-dimethylphenol-7-yl]methanol (example 73) and 4-perbenzoate and was isolated as hydrochloride. The result has been solid white, ISP-MS: m/e=402,5 ([M-Cl]+).

Example 76

Hydrochloride (S)-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-yl]methanol

Specified in the title compound was obtained using the General method described in example 54b, from (4-chloro-2,6-dimethylaniline-7-yl)methanol (example V) and (S)-3-ethoxypyrrolidine (EP 496274) and was isolated as hydrochloride. The result has been a white foam, ISP-MS: m/e=301,4 ([M-Cl]+).

Example 77

Hydrochloride (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 6, of the hydrochloride of (S)-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-yl]methanol (example 76) and 4-perbenzoate and was isolated as hydrochloride. The result has been solid white, ISP-MS: m/e=402,5 ([M-Cl]+).

Example 78

(4-Azepin-1-yl-2,6-dimethylaniline-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 3 from (4-chloro-2,6-dimethylaniline-7-yl)methanol (example V) and azepane. The result has been the foam light brown, ISP-MS: m/e=285,3 ([M+H]+).

Example 79

Formate 4-[(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]-2-triftormetilfosfinov

(a) 2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-carbaldehyde/p>

A mixture containing (2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 59, 140 mg, 0,585 mmol) and manganese dioxide (509 mg, of 5.85 mmol), was stirred in dichloromethane (3 ml) at RT for 16 h, then nerastvorim product was removed by filtration through a bed of dicalite and the filtrate was evaporated, getting mentioned in the title compound (122 mg, 82%) as a solid yellow color, ISP-MS: m/e=255,2 ([M+N]+).

b) Formate 4-[(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]-2-triftormetilfosfinov

Specified in the title compound was obtained using the General method described in example 63A, from 2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-carbaldehyde and 4-amino-2-triftormetilfosfinov and allocated in the form of formate. The result has been solid white, ISP-MS: m/e=425,4 ([M-HCOO]+).

Example 80

(S)-1-(7-Hydroxymethyl-2,6-dimethylaniline-4-yl)pyrrolidin-3-ol

Specified in the title compound was obtained using the General method described in example 54b, from (4-chloro-2,6-dimethylaniline-7-yl)methanol (example V) and (S)-3-pyrrolidinone. The result is a solid white color, ISP-MS: m/e=273,3 ([M+H]+).

Example 81

(2-Chloro-6-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

a) N,N'-bis(3-iodine-4-were)malonamide

The mixture containing diethylmalonate (16.0 g, 100 mmol) and 3-iodine-4-methylaniline (46.6 g, 200 mmol), kept at 210°With whom for 20 min, allowing to evaporate the released ethanol. After cooling, the resulting solid is triturated in hot ethanol (200 ml), receiving specified in the header connection (43,4 g, 81%) as a solid light brown color, ISP-MS: m/e=535,0 ([M+H]+).

b) 4-Hydroxy-7-iodine-6-methyl-1H-quinoline-2-he

N,N'-bis(3-iodine-4-were)malonamide (43,4 g, 81,3 mmol) was added in portions to melt aluminium chloride (32,5 g, 244 mmol) and sodium chloride (9,50 g, 163 mmol) at 150°C, the mixture is then kept at 250°within 20 minutes After cooling, the resulting solid is suspended in hot water and collected by filtration. This crude product is suspended in hot 0.5 M aqueous solution of sodium hydroxide, nerastvorim product was removed by filtration and the filtrate was acidified to a 25%aqueous solution of hydrochloric acid. The precipitate was collected by filtration, washed with water and ethyl acetate and dried, obtaining mentioned in the title compound (6.85 g, 28%) as a solid light brown color, EI-MS: m/e=301,2 (M+).

C) 2,4-Dichloro-7-iodine-6-methylinosine

A mixture containing 4-hydroxy-7-iodine-6-methyl-1H-quinoline-2-he (2.00 g, only 6.64 mmol) and acid chloride phosphoric acid (20 ml)was boiled under reflux for 2 h, then poured on ice and neutralized to pH 7. The precipitate was collected by filtration and dried. The crude about the SPS suspended in ethyl acetate, nerastvorim product was removed by filtration and the filtrate was evaporated, getting mentioned in the title compound (1.80 g, 80%) as a solid orange color EI-MS: m/e=336,9 (M+).

d) Ethyl ester of 2,4-dichloro-6-methylinosine-7-carboxylic acid

Specified in the title compound was obtained using the General method described in example 2 (method B) from 2,4-dichloro-7-iodine-6-methylinosine. The result has been solid white, ISP-MS: m/e=284,1 ([M+H]+).

d) (2-Chloro-6-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 82, of the ethyl ester of 2,4-dichloro-6-methylinosine-7-carboxylic acid and pyrrolidine. The result has been solid white, ISP-MS: m/e=making up 277.3 ([M+H]+).

Example 82

(4-Azepin-1-yl-2-chloro-6-methylinosine-7-yl)methanol

Hydride diisobutylaluminum (1 M solution in tetrahydrofuran, to 4.9 ml, 4.9 mmol) was added dropwise to a solution of ethyl ester of 2,4-dichloro-6-methylinosine-7-carboxylic acid (example 81, 200 mg, 0,704 mmol) in tetrahydrofuran (10 ml), then after 20 min the reaction was stopped by adding 2.5 M aqueous solution of magnesium sulfate (2 ml). Formed within a few seconds the precipitate was removed by filtration and the filtrate was washed with brine, dried (MgSO4) and was evaporated. The remainder ((2,4-dichloro-6-IU is rhinolin-7-yl)methanol) was dissolved in 1 methylpyrrolidine-2-Ohe (3 ml), then added ASEAN (349 mg, to 3.52 mmol) and lithium chloride (119 mg, 2.82 mmol) and the solution kept at 80°C for 16 h, After cooling, was added ethyl acetate and the solution washed with saturated aqueous ammonium chloride and brine solution, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2the gradient of hexane/ethyl acetate) has been specified in the title compound (142 mg, 66%) as a whitish solid, ISP-MS: m/e=305.3 ([M+H]+).

Example 83

Hydrochloride (S)-4-[4-(3-hydroxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile

a) 4-(4-Chloro-2,6-dimethylaniline-7-ylethoxy)benzonitrile

Specified in the title compound was obtained using the General method described in example 54A, from (4-chloro-2,6-dimethylaniline-7-yl)methanol (example V) and 4-perbenzoate. The result has been solid white, ISP-MS: m/e=323,3 ([M+H]+).

b) Hydrochloride (S)-4-[4-(3-hydroxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 54b, from 4-(4-chloro-2,6-dimethylaniline-7-ylethoxy)benzonitrile and (S)-3-pyrrolidinone and was isolated as hydrochloride. The result has been solid white, ISP-MS: m/e=374,5 ([M-Cl]+).

Example 84

(S)-4-[4-(3-Ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-yl is ethoxy]benzonitrile

Sodium hydride (55-65%dispersion in mineral oil, 12 mg, 0.30 mmol) was added to a solution of hydrochloride of (S)-4-[4-(3-hydroxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile (example 83, 58 mg, 0.14 mmol) in N,N-dimethylformamide (1 ml) at 0°With, then after 10 min was added logmean (22 mg, 0.16 mmol). After 90 min the ice bath was removed and the reaction mixture was stirred for another 90 min, then was distributed between dichloromethane and 1 M aqueous sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2CH2Cl2/MeOH/NH4OH, 90:10:0.25) has been specified in the title compound (27 mg, 49%) as a solid white color, ISP-MS: m/e=of 388.4 ([M+H]+).

Example 85

Hydrochloride (S)-1-[2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline-4-yl]pyrrolidin-3-ol

a) 4-Chloro-2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline

A solution containing (4-chloro-2,6-dimethylaniline-7-yl)methanol (example V, 300 mg, 1.35 mmol), 3,4-dihydro-2H-Piran (342 mg, 4,06 mmol) and toluene-4-sulfonate pyridinium (374 mg, 1,49 mg) in dichloromethane (3 ml) and toluene (3 ml)was stirred at RT for 3 days, then was distributed between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2 the gradient of hexane/ethyl acetate) has been specified in the title compound (243 mg, 59%) as a solid white color, ISP-MS: m/e=306,3 ([M+H]+).

b) hydrochloride (S)-1-[2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline-4-yl]pyrrolidin-3-ol

Specified in the title compound was obtained using the General method described in example 54b, from 4-chloro-2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline and (S)-3-pyrrolidinone and was isolated as hydrochloride. The result has been solid white, ISP-MS: m/e=357,4 ([M-Cl]+).

Example 86

(S)-4-(3-Ethoxypyrrolidine-1-yl)-2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline

Specified in the title compound was obtained using the General method described in example 84, from the hydrochloride of (S)-1-[2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline-4-yl]pyrrolidin-3-ol (example 85) and iodomethane. The result obtained colorless resin, ISP-MS: m/e=371,4 ([M+H]+).

Example 87

(6-Methoxy-2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

a) 4-Chloro-7-iodine-6-methoxy-2-methylinosine

Specified in the title compound was obtained using the General method described in example 59A, 3-iodine-4-methoxyaniline (J. Chem. Soc. Perkin 2, 1980, C) and was separated from the isomer 4-chloro-5-iodine-6-methoxy-2-methylinosine using Express chromatography (SiO2the gradient of hexane/ethyl acetate). The result has been t ardoe substance of white color, ISP-MS: m/e=334,1 ([M+H]+).

b) Ethyl ester of 4-chloro-6-methoxy-2-methylinosine-7-carboxylic acid

Specified in the title compound was obtained using the General method described in example 2 (method B)from 4-chloro-7-iodine-6-methoxy-2-methylinosine. The result has been a solid light brown color, ISP-MS: m/e=280,2 ([M+H]+).

in) (4-Chloro-6-methoxy-2-methylinosine-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 2B, ethyl ester 4-chloro-6-methoxy-2-methylinosine-7-carboxylic acid. The result has been solid white, EI-MS: m/e=USD 237.2 (M+).

g) (6-Methoxy-2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 2 g of (4-chloro-6-methoxy-2-methylinosine-7-yl)methanol and pyrrolidine. The result has been solid white, ISP-MS: m/e=273,3([M+H]+).

Example 88

(6-Methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

a) Ethyl ester of 7-iodine-6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A mixture containing 3-iodine-4-methylaniline (10.0 g, 42,9 mmol) and diethylethylenediamine (12.4 g, 57,2 mmol), kept at 150°C for 80 min and allowed to evaporate released ethanol. After cooling, was added Dowtherm® A (50 ml), the mixture is then kept at 50° C for 75 min After cooling to room temperature was added heptane (50 ml) and the precipitate was collected by filtration. The crude product is sequentially triturated in hexane/ethyl acetate (50 ml) and 70%aqueous ethanol (2×300 ml), receiving specified in the header connection (8,30 g, 54%) as a solid white color, ISP-MS: m/e=358,1 ([M+H]+).

b) 7-Iodine-6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A suspension of ethyl ester of 7-iodine-6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8,30 g, 23.2 mmol) in 2 M aqueous sodium hydroxide solution (80 ml) was boiled under reflux for 2 hours, After cooling the resulting solution was acidified to a 25%aqueous solution of hydrochloric acid. The precipitate was collected by filtration and dried, obtaining specified in the header connection (7,56 g, 99%) as a solid white color, ISN-MS: m/e=327,9 ([M-H]-).

C) 7-Iodine-6-methyl-1H-quinoline-4-one

Under vigorous stirring was added by portions 7-iodine-6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6.50 g, and 19.8 mmol) to Dowtherm® A (120 ml) at 250°C, then the mixture was stirred for another 90 minutes After cooling was added heptane (170 ml) and the precipitate was collected by filtration. The crude product is triturated in hexane/ethyl acetate (1:1), obtaining specified in the header connection (5,12 g, 91%) as a whitish solid, ISP-MS: m/e=286,1 ([M+H]+ ).

g) 4-Chloro-7-iodine-6-methylinosine

A mixture containing 7-iodine-6-methyl-1H-quinoline-4-one (5,12 g, 18.0 mmol), acid chloride phosphoric acid (14 ml) and N,N-dimethylformamide (1 ml) was stirred at 60°C for 80 min, then poured onto ice and carefully neutralized to a 25%aqueous solution of ammonium hydroxide. The suspension was extracted three times with dichloromethane, the combined organic phase was washed with brine, dried (MgSO4) and was evaporated, getting mentioned in the title compound (5,33 g, 98%) as a solid light brown color, ISP-MS: m/e=304,1 ([M+H]+).

e) Ethyl ether 4-chloro-6-methylinosine-7-carboxylic acid

Specified in the title compound was obtained using the General method described in example 2 (method B)from 4-chloro-7-iodine-6-methylinosine. The result has been solid brown, ISP-MS: m/e=250,2 ([M+H]+).

e) (4-Chloro-6-methylinosine-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 2B, ethyl ester 4-chloro-6-methylinosine-7-carboxylic acid. The result has been a whitish solid, EI-MS: m/e=189,3 ([M-H2O]+, 100%), 207,2 (M+, 34%).

W) (6-Methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 2 g of (4-chloro-6-METHYLPHENOL the n-7-yl)methanol and pyrrolidine. The result has been a solid light brown color, ISP-MS: m/e=243,2 ([M+H]+).

Example 89

(S)-[4-(3-Ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-yl]methanol

A solution containing (S)-4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline (example 86, 50 mg, 0.14 mmol) and toluene-4-sulfonate pyridinium (37 mg, 0.15 mmol) was stirred at 70°C for 16 h, then was distributed between ethyl acetate and 1 M aqueous sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2CH2Cl2/MeOH/NH4OH, 90:10:0.25) has been specified in the title compound (26 mg, 67%) as a solid white color, ISP-MS: m/e=287,2 ([M+H]+).

Example 90

4-((S)-3-(Cyclopropylmethoxy)pyrrolidin-1-yl)-2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline

Specified in the title compound was obtained using the General method described in example 84, from the hydrochloride of (S)-1-[2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline-4-yl]pyrrolidin-3-ol (example 85) and (methyl bromide)cyclopropane. The result obtained colorless resin, ISP-MS: m/e=371,4 ([M+H]+).

Example 91

4-Azepin-1-yl-2-chloro-6-methyl-7-(3-triftormetilfullerenov)quinoline

Diisopropylsalicylic (66 mg, 0.33 mmol) was added dropwise at RT to a solution containing(4-azepin-1-yl-2-chloro-6-methylinosine-7-yl)methanol (example 82, 100 mg, 0.33 mmol), 3-triptoreline (53 mg, 0.33 mmol) and triphenylphosphine (86 mg, 0.33 mmol) in dichloromethane (2 ml), then after 2 h was added ethyl acetate and the solution washed with 1 M aqueous sodium hydroxide solution and with brine, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2the gradient of hexane/ethyl acetate) has been specified in the title compound (118 mg, 80%) as a solid white color, ISP-MS: m/e=449,4 ([M+H]+).

Example 92

(S)-4-{[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-ylmethyl]amino}benzonitrile

a) 4-[(4-Chloro-2-methylinosine-7-ylmethyl)amino]benzonitrile

Triacetoxyborohydride sodium (74 mg, 0.34 mmol) was added to a solution containing 4-chloro-2-methylinosine-7-carbaldehyde (example 13A, 50 mg, 0.24 mmol), 4-aminobenzonitrile (29 mg, 0.24 mmol) and acetic acid (88 mg, 1.5 mmol) in 1,2-dichloroethane (0.5 ml), then after 16 h the reaction mixture was distributed between ethyl acetate and 2 M aqueous solution of sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2, hexane/ethyl acetate, 1:1) has been specified in the title compound (48 mg, 64%) as a solid white color, ISP-MS: m/e=308,2 ([M+H]+).

b) (S)-4-{[4-(3-Ethoxypyrrolidine-1-yl)-2-methylinosine-7-ylmethyl]amino}benzonitrile

Specified in the header of the floor connection is made using the General method, described in example 54b, from 4-[(4-chloro-2-methylinosine-7-ylmethyl)amino]benzonitrile and (S)-3-ethoxypyrrolidine. The result has been a white foam, ISP-MS: m/e=387,3 ([M+H]+).

Example 93

(S)-4-[4-(3-Ethoxypyrrolidine-1-yl)-2-methylin-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 54b, from 4-(4-chloro-2-methylinosine-7-ylethoxy)benzonitrile (example 54A) and (S)-3-ethoxypyrrolidine. The result has been a white foam, ISP-MS: m/e=388,3 ([M+H]+).

Example 94

(S)-[4-(3-(cyclopropylmethoxy)pyrrolidin-1-yl)-2,6-dimethyl-quinoline-7-yl]methanol

Specified in the title compound was obtained using the General method described in example 89, of 4-((S)-3-(cyclopropylmethoxy)pyrrolidin-1-yl)-2,6-dimethyl-7-(tetrahydropyran-2-intoximeter)quinoline (example 90). The result has been solid light yellow color, ISP-MS: m/e=327,4 ([M+H]+).

Example 95

N-[4-Azepin-1-yl-6-methyl-7-(3-triftormetilfullerenov)quinoline-2-yl]methylamine

Specified in the title compound was obtained using the General method described in example 96, 4-azepin-1-yl-2-chloro-6-methyl-7-(3-triftormetilfullerenov)quinoline (example 91) and methylamine. The result has been solid light yellow color, ISP-MS: m/e=444,5 ([M+H]+).

Example 96

[4-Azepin-1-yl-6-methyl-7-(3-triftormetilfullerenov)hee the Olin-2-yl]dimethylamine

A mixture containing 4-azepin-1-yl-2-chloro-6-methyl-7-(3-triftormetilfullerenov)quinoline (example 91, 56 mg, 0.13 mmol) and 33%ethanolic solution of dimethylamine (4 ml), kept at 157°C for 2 h in a sealed tube, exposing to microwave radiation. After cooling the resulting solution was distributed between dichloromethane and 2 M aqueous solution of sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Using Express chromatography (CH2Cl2/MeOH/NH4OH, a 97.5:2.5 to:0,2) has been specified in the title compound (45 mg, 79%) as a whitish solid, ISP-MS: m/e=458,5 ([M+H]+).

Example 97

(4-Azepin-1-yl-2-dimethylamino-6-methylinosine-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 96, from (4-azepin-1-yl-2-chloro-6-methylinosine-7-yl)methanol (example 82) and dimethylamine. The result has been solid light yellow color, ISP-MS: m/e=314.4 M. ([M+H]+).

Example 98

(S)-4-[4-(3-(Cyclopropylmethoxy)pyrrolidin-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 84, from the hydrochloride of (S)-4-[4-(3-hydroxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile (example 83) and (methyl bromide)cyclopropane. In the received pen is yellow, ISP-MS: m/e=to 428.6 ([M+H]+).

Example 99

4-(6-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile

Specified in the title compound was obtained using the General method described in example 6 from (6-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 88) and 4-perbenzoate. The result has been a whitish solid, ISP-MS: m/e=to 344.4 ([M+H]+).

Example 100

4-(4-Azepin-1-yl-2-dimethylamino-6-methylinosine-7-ylethoxy)benzonitrile

Specified in the title compound was obtained using the General method described in example 6 from (4-azepin-1-yl-2-dimethylamino-6-methylinosine-7-yl)methanol (example 97) and 4-perbenzoate. The result has been a whitish solid, ISP-MS: m/e=415,5 ([M+H]+).

Example 101

4-[(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile

a) 4-Chloro-2,6-dimethylaniline-7-carbaldehyde

Specified in the title compound was obtained using the General method described in example 13 (method A), from (4-chloro-2,6-dimethylaniline-7-yl)methanol (example V). The result has been solid white, ISP-MS: m/e=to 220.3 ([M+H]+).

b) 4-[(4-Chloro-2,6-dimethylaniline-7-ylmethyl)amino]benzonitrile

Specified in the title compound was obtained using the General method described in example 92A, from 4-chloro-2,6-dimethylaniline-7-carbaldehyde and 4-aminobenzonitrile. The result has been solid prophetic the STV white, ISP-MS: m/e=was 322.3 ([M+H]+).

C) 4-[(2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile

Specified in the title compound was obtained using the General method outlined in example 56, 4-[(4-chloro-2,6-dimethylaniline-7-ylmethyl)amino]benzonitrile and pyrrolidine. The result obtained foam is light yellow in color, ISP-MS: m/e=357,3 ([M+H]+).

Example 102

(S)-4-{[4-(3-Ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylmethyl]amino}benzonitrile

Specified in the title compound was obtained using the General method described in example 54b, from 4-[(4-chloro-2,6-dimethylaniline-7-ylmethyl)amino]benzonitrile (example 101B) and (S)-3-ethoxypyrrolidine. The result obtained foam is light yellow in color, ISP-MS: m/e=is 401.5 ([M+H]+).

Example 103

4-(6-Methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-2-cryptomathematical

Specified in the title compound was obtained using the General method described in example 6 from (6-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol (example 88) and 4-fluoro-2-triftormetilfosfinov. The result has been solid yellow, ISP-MS: m/e=412,3 ([M+H]+).

Example 104

(S)-[4-(3-Ethoxypyrrolidine-1-yl)-6-methylinosine-7-yl]methanol

Specified in the title compound was obtained using the General method described in example 54b, from (4-chloro-6-methyl-quinoline-7-yl)methanol (example e) and (S)-3-ethoxypyrrolidine. In the floor of the Ali solid yellow, ISP-MS: m/e=287,2 ([M+H]+).

Example 105

(S)-4-{[4-(2-Hydroxyethylpyrrolidine-1-yl)-2,6-dimethylphenol-7-ylmethyl]amino}benzonitrile

Specified in the title compound was obtained using the General method described in example 54b, from 4-[(4-chloro-2,6-dimethylaniline-7-ylmethyl)amino]benzonitrile (example 101B) and L-prolinol. The result obtained foam is light yellow in color, ISP-MS: m/e=387,3 ([M+H]+).

Example 106

4-[(2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)methylamino]benzonitrile

a) 4-[(4-Chloro-2,6-dimethylaniline-7-ylmethyl)methylamino]benzonitrile

Logmean (46 mg, 0.33 mmol) was added to a solution of 4-[(4-chloro-2,6-dimethylaniline-7-ylmethyl)amino]benzonitrile (example 101B, 70 mg, 0.22 mmol) in N,N-dimethylformamide (1 ml) at 0°C. the Reaction mixture was stirred for 1 h at 0°C and 1 h at RT, then was distributed between dichloromethane and 1 M aqueous sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Using Express chromatography (SiO2, hexane/ethyl acetate, 2:1, then 1:1) has been specified in the title compound (63 mg, 86%) as a solid white color, ISP-MS: m/e=336,2 ([M+H]+).

b) 4-[(2,6-Dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)methylamino]benzonitrile

Specified in the title compound was obtained using the General method outlined in example 56, 4-[(4-chloro-2,6-dimethyl shall inolin-7-ylmethyl)methylamino]benzonitrile and pyrrolidine. The result has been solid white, ISP-MS: m/e=371,3 ([M+H]+).

Example 107

(S)-4-[4-(3-Ethoxypyrrolidine-1-yl)-6-methylinosine-7-ylethoxy]benzonitrile

Specified in the title compound was obtained using the General method described in example 6, from (S)-[4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-yl]methanol (example 104) and 4-perbenzoate. The result has been solid yellow, ISP-MS: m/e=388,2 ([M+H]+).

Example 108

Hydrochloride (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-6-metalchain-7-ylethoxy]-2-triftormetilfosfinov

Specified in the title compound was obtained using the General method described in example 6, from (S)-[4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-yl]methanol (example 104) and 4-fluoro-2-triftormetilfosfinov. The result has been solid white, ISP-MS: m/e=456,4 ([M-Cl]+).

Example 109

a) (S)-4-(3-Ethoxypyrrolidine-1-yl)-6-methylinosine-7-carbaldehyde

Specified in the title compound was obtained using the General method described in example 79A, (S)-[4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-yl]methanol (example 104). The result has been a solid dark green color, ISP-MS: m/e=285,1 ([M+H]+).

b) (S)-4-{[4-(3-Ethoxypyrrolidine-1-yl)-6-methylinosine-7-ylmethyl]amino}-2-cryptomathematical

Specified in the title compound was obtained using the General method is as, described in example 92A, (S)-4-(3-ethoxypyrrolidine-1-yl)-6-methylinosine-7-carbaldehyde and 4-amino-2-triftormetilfosfinov. The result obtained resin, light brown, ISP-MS: m/e=455,4 ([M+H]+).

Example 110

(S)-4-{[4-(3-Ethoxypyrrolidine-1-yl)-6-methylinosine-7-ylmethyl]amino}benzonitrile

Specified in the title compound was obtained using the General method described in example 92A, (S)-4-(3-Ethoxypyrrolidine-1-yl)-6-methylinosine-7-carbaldehyde (example 109) and 4-aminobenzonitrile. The result has been solid white, ISP-MS: m/e=387,2 ([M+H]+).

Example 111

Methyl ester of 6-bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid

a) 4-Bromo-3-methoxybenzylamine

The suspension containing iron powder (40,8 g, at 0.730 mol), ammonium chloride (64,7 g to 1.21 mol) and 2-bromoanisole (50 g, 0,215 mol) in water (1.5 l) and Meon (1 l)was stirred overnight at 75°C. the Solid was filtered and the liquid was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and the solvents evaporated under vacuum, the result has been to 43.1 g specified in the connection header in a solid brown color, ISP-MS: m/e=203,1 ([M+H]+).

b) 5-Amino-2-bromophenol

The suspension containing 4-bromo-3-methoxybenzylamine (37.6 g, 0,186 mol) and tetrabutylammonium iodide (96 g, is 0.260 mol) in d is chlormethine (1.2 l), was cooled to -78°C. was Added dropwise within 20 min 1 M solution of trichloride boron in dichloromethane (520 ml, 0,521 mol). The cooling bath was removed. After 3 h the reaction mixture was poured into ice water (4.5 kg). The organic layer was extracted with water. The combined aqueous layers were washed with dichloromethane. The pH was brought to 9 with sodium bicarbonate. Was added sodium chloride to saturation. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvents evaporated. The solid is washed with dichloromethane and dried in vacuum. Received of 35.2 g specified in the connection header in a solid brown color, ISP-MS: m/e=189,1 ([M+H]+).

C) 3-Benzyloxy-4-brompheniramine

To a solution of 5-amino-2-bromophenol (35.2 g, 0,187 mol) in N,N-dimethylformamide (350 ml) was added tert-piperonyl potassium (22.9 grams, 0,204 mol). After 15 min for 2 min was added benzylchloride (25,5 ml, 0,222 mol). The reaction mixture was stirred for 4 h and then was poured into aqueous sodium bicarbonate solution and was extracted with ethyl acetate.

The combined organic phases were washed with brine and water, then dried over sodium sulfate, filtered and evaporated in vacuum. Received 55,6 g specified in the connection header in a solid black color, ISP-MS: m/e=279,1 ([M+H]+ ).

d) Ethyl ester of 3-(3-benzyloxy-4-brompheniramine)but-2-ene acid

To a mixture containing 3-benzyloxy-4-brompheniramine (55.7 g, has 0.168 mol) and ethylacetoacetate (and 23.4 ml, 0.185 mol) in cyclohexane was added monohydrate toluene-4-sulfonic acid (0,320 g, by 1.68 mmol). The reaction mixture is boiled under reflux for 6 h and then azeotropically removed the water. Then the reaction mixture was distributed between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and the solvents evaporated in vacuo. Got to 69.6 g specified in the connection header in the form of oil black, ISP-MS: m/e=392,2 ([M+H]+).

d) 7-Benzyloxy-6-bromo-2-methylinosine-4-ol

Dowtherm®A (320 ml) was heated to 250°and then was slowly added a solution of ethyl ester of 3-(3-benzyloxy-4-brompheniramine)but-2-ene acid (of 55.5 g of 99.5 mmol) in Dowtherm®A (120 ml). The reaction mixture was stirred for 16 min at 250°and the ethanol was collected by distillation. The mixture was cooled, was diluted in hexane (1.5 l) and filtered. The solid is washed with a simple ether and dried in vacuum. Received 73,0 g specified in the connection header in a solid brown color, ISP-MS: m/e=345,2 ([M+H]+).

e) 7-Benzyloxy-6-bromo-4-chloro-2-methylinosine

7-Benzyloxy-6-bromo-2-matilha the Olin-4-ol (25,0 g, to 72.6 mmol) and acid chloride phosphoric acid (70 ml, 0,764 mol) was kept for 40 min at 130°and then cooled to room temperature. The acid chloride phosphoric acid is evaporated in a high vacuum. Added ice and the pH value of this solution was brought to 9 with ammonium hydroxide. The suspension was extracted with dichloromethane. The combined organic layers was dried in vacuum. Received 22,8 g specified in the connection header in a solid brown color, ISP-MS: m/e=364,0 ([M+H]+).

g) 7-Benzyloxy-6-bromo-2-methyl-4-pyrrolidin-1-rhinolin

A mixture containing 7-benzyloxy-6-bromo-4-chloro-2-methylinosine (10.0 g, 27.6 mmol) and pyrrolidine (47 ml, 0,562 mol), was heated under reflux for 3 hours the Mixture was cooled and pyrrolidin evaporated in high vacuum. The residue was dissolved in dichloromethane, washed with water and with brine, dried over sodium sulfate, filtered and the solvents evaporated in vacuo. Received 6,9 g specified in the connection header in a solid brown color, ISP-MS: m/e=399,2 ([M+H]+).

C) 6-Bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-ol

To a cooled (0° (C) a solution of 7-benzyloxy-6-bromo-2-methyl-4-pyrrolidin-1-rhinolin (2.3 g, 5,79 mmol) in dichloromethane (70 ml) was added within 20 min 1 M solution of titanium tetrachloride in dichloromethane (48.6 ml, 48.6 per mmol). After 1 h actionnow mixture was poured into aqueous sodium bicarbonate solution, was extracted with dichloromethane and evaporated. Received 1.13 g specified in the connection header in a solid yellow color, ISP-MS: m/e=308,1 ([M+H]+).

and) 6-Bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-silt ether pyrrolidineethanol acid

To a cooled (-25° (C) a solution of 6-bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-ol (350 mg, to 1.14 mmol) and triethylamine (0,189 ml, 2,62 mmol) in dichloromethane (1.5 ml) was added within 20 min anhydride triftormetilfullerenov (0,292 ml, 1.37 mmol). The cooling bath was removed and the reaction mixture was stirred over night. The mixture was poured into aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvents evaporated in vacuo. Received 341 mg specified in the connection header in a solid brown color, ISP-MS: m/e=440,2 ([M+H]+).

C) Methyl ester of 6-bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid

The suspension containing 6-bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-silt ether pyrrolidineethanol acid (160 mg, 0,364 mmol), triethylamine (0,030 μl, 0.4 mmol), palladium acetate (8 mg, being 0.036 mmol) and bis(1,3-diphenylphosphino)propane (16 mg, 0,039 mmol) in dimethylsulfoxide (0.5 ml) and methanol (0.4 ml), was heated in an atmosphere of carbon monoxide to 65°C for 90 minutes the Reaction mixture is poured on an aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvents were removed in vacuum. Received 124 mg specified in the connection header in a solid brown color, ISP-MS: m/e=429,2 ([M+H]+).

Example 112

(6-Bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanol

Specified in the title compound was obtained using the General method described in example 2B, of the methyl ester of 6-bromo-2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid (example 111). The result has been solid light yellow color, ISP-MS: m/e=321,2 ([M+H]+).

Example

The compound of the formula I can be used as an active substance for the preparation of a well-known method of tablets of the following composition:

Pills

the active ingredient200 mg
microcrystalline cellulose155 mg
corn starch25 mg
talc25 mg
the hypromellose20 mg
425 mg

Example B

The compound of the formula I can be used as an active substance for the preparation of a well-known method of capsules of the following composition:

On capsule

the active ingredient100.0 mg
corn starch20.0 mg
lactose95,0 mg
talc4.5 mg
magnesium stearate0.5 mg
220,0 mg

The example In

Tablets containing the following ingredients, can be prepared by usual method:

IngredientsPills
the compound of the formula Iof 10.0-100.0 mg
lactose125,0 mg
corn starch75,0 mg
talc4.0 mg
magnesium stearate1.0 mg

Example D

Capsules containing the following ingredients, can be prepared by usual method:

IngredientsOn capsule
the compound of the formula I25.0 mg
lactose150,0 mg
corn starch20.0 mg
talc5.0 mg

Example D

Injectable solutions may have the following composition:

link the formula I 3.0 mg
gelatin150,0 mg
phenol4,7 mg
water for injectable solutionsto 1.0 ml

1. The compounds of formula I

where R1denotes-O-R4or-NR5R6;

R2denotes hydrogen, alkyl, alkoxy and halogen;

R3denotes alkyl or halogen;

R4denotes hydrogen, alkyl, phenyl, phenyl substituted by 1-3 substituents, independently of one another selected from the series comprising alkyl, cyano, trifluoromethyl, alkoxy, halogen, pyrrolidinylcarbonyl and nitro, alkoxyalkyl or heterocyclyl, which denotes a saturated or aromatic 4-10-membered heterocycle containing one heteroatom selected from nitrogen, oxygen;

R5and R6independently from each other chosen from the series comprising hydrogen, alkyl or phenyl;

or R5and R6together with the N atom to which they are attached, form a 5-to 10-membered heterocyclic ring, optionally containing a nitrogen atom;

And1represents a 5-7 membered saturated heterocyclic ring which contains the nitrogen atom attached to the quinoline ring, and optionally a second nitrogen atom, and where the ring is optionally substituted 1-zamestitelyami, independently of one another selected from the series comprising alkyl, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, tetrahydropyranyloxy, cycloalkylcarbonyl;

And2denotes-CH2- or-C(O)-,

where the alkyl individually or in combination, refers to an alkyl group in a straight chain which contains 1-8 carbon atoms;

and their pharmaceutically acceptable salts and complex alkalemia esters.

2. Compounds according to claim 1, where a1represents a 5-7 membered saturated heterocyclic ring containing the nitrogen atom attached to the quinoline ring, and optionally a second nitrogen atom, and where the ring is optionally substituted by 1-3 substituents, independently of one another selected from the series comprising alkyl, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, tetrahydropyranyloxy, cycloalkylation.

3. Compounds according to claim 1 or 2, where R2denotes hydrogen or methyl.

4. Compounds according to claim 1 or 2, where R1denotes-O-R4.

5. Compounds according to claim 1 or 2, where R1refers to-NR5R6.

6. Compounds according to claim 1 or 2, where R3denotes alkyl.

7. Compounds according to claim 6, where R3denotes methyl.

8. Compounds according to claim 1 or 2, where R4denotes hydrogen, alkyl, phenyl, phenyl substituted by 1-3 substituents, independently of one another selected from the series vkljuchajuwih is alkyl, cyano, trifluoromethyl, alkoxy, halogen, pyrrolidinylcarbonyl and nitro.

9. Compounds according to claim 1 or 2, where one of R5and R6denotes hydrogen or phenyl, and the other denotes hydrogen or alkyl; or R5and R6together with the N atom to which they are attached, form a pyrolidine ring.

10. Compounds according to claim 1 or 2, where a1represents a 5-7 membered saturated heterocyclic ring containing a nitrogen atom that is attached to the quinoline ring, and where the optional second nitrogen atom present in the ring and where the ring is optionally substituted by alkyl.

11. Connection of claim 10, where a1means pyrolidine, piperidine, asianave, pieperazinove, pyrolidine or [1,4]diazepinone ring, optionally substituted alkyl.

12. Compounds according to claim 1 or 2, where a2denotes-CH2-.

13. Compounds according to claim 1, selected from the series comprising (4-azepin-1-yl-2-methylinosine-7-yl)methanol, 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile, 4-(4-azepin-1-yl-2-methylinosine-7-ylethoxy)benzonitrile, 4-[(2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile, 2-methyl-7-(pyridine-4-intoximeter)-4-pyrrolidin-1-rhinolin, butylamide 2-methyl-4-pyrrolidin-1-rhinolin-7-carboxylic acid, 2-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile, 2-chloro-4-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl is ethoxy)benzonitrile, 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)-2-cryptomathematical, 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)phthalonitrile,(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)methanol, 4-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylethoxy)benzonitrile, 4-[(2-methyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]-2-cryptomathematical, (S)-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-yl]methanol, (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylethoxy]benzonitrile, 4-[(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-ylmethyl)amino]benzonitrile, (S)-4-{[4-(3-ethoxypyrrolidine-1-yl)-2,6-dimethylphenol-7-ylmethyl]amino}benzonitrile.

14. The method of obtaining the compounds according to one of claims 1 to 13, characterized in that the compound of the formula Q1 is subjected to interaction in the presence of an amine of the formula Q2 obtaining the compounds of formula Q3

where R1, R2And1and2have the meanings indicated in claim 1, and R30denotes hydrogen, alkyl or halogen and Y represents chlorine, bromine or iodine.

15. The method of obtaining the compounds according to one of claims 1 to 13, characterized in that the compound of formula H is subjected to interaction in the presence of hydrogen peroxide to obtain the compounds of formula ID

where R2and1have the meanings indicated in claim 1 and R30denotes hydrogen, al is silt or halogen.

16. The method of obtaining the compounds according to one of claims 1 to 13, characterized in that the compound of formula IE is subjected to interaction in the presence of hydride to obtain the compounds of formula IF

where R2, R5, R6and1have the meanings indicated in claim 1, and where R30denotes hydrogen, alkyl or halogen.

17. The method of obtaining the compounds according to one of claims 1 to 13, characterized in that the compound of formula IJ is subjected to interaction in the presence of an appropriate amine HNR'R" with obtaining the compounds of formula IK

where R1, R2And1and2have the meanings indicated in claim 1, and R' and R" independently from each other selected from hydrogen, alkyl and picoalgae, or R' and R" together with the N atom to which they are attached, form a 5-to 10-membered heterocyclic ring, where the heterocyclic ring optionally substituted by one or more substituents, independently from each other selected from alkyl and alkoxygroup, and Y denotes a chlorine, bromine or iodine.

18. Compounds according to claim 1, intended for use as an antagonist against neuropeptide Y.

19. Compounds according to claim 1, intended for the preparation of drugs for the prevention and treatment of diseases that are associated with violations, poreuomai NPY receptor.

20. Pharmaceutical composition having antagonistic activity against neuropeptide Y-containing compound according to one of claims 1 to 13 and a therapeutically inert carrier.

21. Compounds according to claim 1, obtained according PP-17.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula: or their pharmaceutically acceptable salts wherein Ra - R8a mean phenyl; R8b means pyridyl, or R8 means naphthyl; R1 means hydrogen atom; R2 - R9, R10, R11 mean substituted phenyl; R9, R10, R11 mean substituted pyridyl or pyrimidyl; R9, R10, R11 mean substituted pyridyl-N-oxide or pyrimidyl-N-oxide; R12, R13 mean substituted oxazolyl, naphthyl, fluorenyl, compounds of formulae , or ; R3 means hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl; R8 means phenyl; R8 means phenyl-(C1-C6)-alkyl, or R8 means thienyl-(C1-C6)-alkyl; R4, R5, R7 and R13 mean independently hydrogen atom or (C1-C6)-alkyl; R6 means hydrogen atom or (C1-C6)-alkyl; R8 means 1-3 substitutes that mean independently hydrogen atom, halogen atom, (C1-C6)-alkoxyl or -CF3; R8a means 1-3 substitutes that mean independently hydrogen atom, halogen atom, -CF3, -CF3O, -CN; R14 means phenyl, -NHCOCF3 and imidazolyl; R8b means 1-3 substitutes that mean independently hydrogen atom or halogen atom; R9 and R10 mean independently (C1-C6)-alkyl, halogen atom, -NR17R18, -OH, -CF3 and -OCH3; R11 means R9, hydrogen atom, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CN=NOR17, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, -N(R17)CONR18R19, -NHCONH-(chloro-(C1-C6)-alkyl), -NHCONH-((C3-C10)-cycloalkyl-(C1-C6)-alkyl), -NHCO-(C1-C6)-alkyl, -NHCOCF3, -NHSO2N-((C1-C6)-alkyl)2, -NHSO2-(C1-C6)-alkyl, -N(SO2CF3)2, -NHCO2-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, -SR20, -OSO2-(C1-C6)-alkyl, -SO2CF3, hydroxy-(C1-C6)-alkyl, -CONR17R18, -CON(CH2CH2-O-CH3)2, -OCONH-(C1-C6)-alkyl, -Si(CH3)3 or -B(OC(CH3)2)2; R12 means (C1-C)-alkyl or R14-phenyl; R14 means 1-3 substitutes that mean independently hydrogen, (C1-C6)-alkyl, -CF3, -CO2R17, -CN, (C1-C6)-alkoxyl and halogen atom; R15 and R16 mean independently hydrogen atom and (C1-C6)-alkyl, or R15 and R16 mean in common (C2-C5)-alkylene group and in common with carbon atom to which they are bound form (C3-C6)-spiran ring; R17, R18 and R19 mean independently hydrogen atom or (C1-C6)-alkyl; R20 means (C1-C6)-alkyl. Also, invention describes pharmaceutical compositions containing these compounds and using novel compounds as CCR5 antagonists in treatment of HIV infection, arthritis, asthma, cerebrospinal sclerosis and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

29 cl, 30 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of quinoline of the formula (I): wherein R1 and R2 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, phenyl, unsubstituted benzyl or benzyl substituted with halogen atom, cyano-group, trifluoromethyl, alkyl, alkoxy-group, benzylcarbonyl, pyridinyl, furyl, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-, thiophenyl-SO2; or R1 and R2 in common with atom N to which they are added form piperidino-group, pyrrolidinyl, morpholinyl, azepanyl, 3,4-dihydro-1H-isoquinolinyl, and wherein heterocyclic ring is optionally substituted with one or some substitutes chosen independently from alkyl and alkoxy-group; R3 represents hydrogen atom, alkyl; R4 represents hydrogen atom; A in common with nitrogen atom that is added to quinoline ring represents pyrrolidinyl, azepanyl, and ring A is optionally substituted with one-three substitutes chosen independently from alkoxy-group, hydroxyalkyl, alkoxyalkyl. Also, invention describes methods of synthesis of quinoline derivatives of the formula (I). Proposed compounds can be used as components of pharmaceutical formulations in treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes mellitus, renal insufficiency, disorders in food eating and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 122 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 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, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

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

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes perfluoroalkyl-containing complexes with polar residues of the general formula (I):

wherein R means a polar residue; G means a trifunctional residue, a perfluorinated carbon chain; K means a metal complex; Z means a linker group. Proposed complexes can be used for intravenous lymphography, tumor diagnosis and for visualization of infarctions and necrosis. Also, invention describes a method for synthesis of these complexes.

EFFECT: valuable medicinal properties of complexes.

16 cl, 1 tbl, 26 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to chemistry of biologically active substances, in particular, to novel biologically active compounds, namely, 2-(5-R-aminomethylfuryl-2)-1,3-dioxalanes of the formula (I): wherein at (Ia) R means --Ts and at (Ib) R means -CO-Ph. These compounds show properties as activating agent with respect to germination of winter wheat grains of sort "Pobeda-50" possessing growth-regulating and anti-stress activity.

EFFECT: valuable biological properties of compounds.

1 cl, 2 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

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

SUBSTANCE: invention relates to novel derivatives of varioline and their pharmaceutically acceptable salts and esters possessing anti-tumor activity. In compound of the formula (I): each among R1 and R2 is chosen independently from group comprising hydrogen atom (H), -OH, -OR', -SH, -SR', -SOR', -SO2R', -NO2, -NH2, -NHR', -N(R')2, -NHCOR'. -N-(COR')2, -NHSO2R', (C1-C12)-alkyl, (C1-C12)-halogenalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaromatic group; R3 is chosen from group comprising -OH and -OMe wherein group R' or each among groups R' is chosen independently from group comprising -OH, (C1-C12)-alkyl, (C1-C12)-halogenalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl and substituted or unsubstituted heteroaromatic group; if group R1 or R2 represents group of the formula -N(R')2 or -N(COR')2 then all groups R' can comprise similar or different values, either groups R' in common with nitrogen atom to which they are added can form 5-7-membered heterocyclic ring. Aryl group or aryl moiety of aralkyl and arylalkenyl group represents a carbocyclic aryl group comprising 6 carbon atoms in carbocyclic ring; aralkyl group represents (C1-C6)-alkyl group substituted with abovementioned aryl group; arylalkenyl group represents (C2-C6)-alkenyl group substituted with abovementioned aryl group; heteroaromatic group represents a heterocyclic aromatic group comprising from 5 to 7 atoms in ring wherein heteroatoms in ring are chosen from nitrogen atom; substituted in aryl and heteroaromatic groups and in aryl moiety of aralkyl and arylalkenyl groups are chosen from group comprising (C1-C12)-alkyl, (C1-C12)-halogenalkyl, (C1-C12)-alkoxy-, (C1-C12)-alkylthio-group, -NH2, (C1-C6)-alkylamino-, di-(C1-C6)-alkyl)-amino-, (C1-C4)-alkanoylamino-, di-(C1-C4)-alkanoylamino-group, -NO2, -CN and halogen atom, its derivatives wherein nitrogen atom is quaternized. Proposed compounds possess anti-tumor activity and can be used in treatment or prophylaxis of cancerous diseases, for example, ovary cancer, prostate cancer, mammary cancer and melanoma.

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

38 cl, 10 sch, 2 tbl, 25 ex

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to anthranylamidepyridine amides of selective effect as inhibitors of VEGFR-2 and VEGFR-3. Invention describes compounds of the general formula (I): wherein A, B and D represent independently of one another nitrogen atom or carbon atom wherein at least one nitrogen atom is in a ring; E represents aryl comprising 6-12 ring carbon atoms or heteroaryl comprising 5 or 6 ring atoms and comprising in ring instead carbon atom similar or different heteroatoms chosen from nitrogen or sulfur atoms, or represents group -COOR8, -CONR2R3 or -C≡C-R9; G represents nitrogen atom or group -C-X; L represents nitrogen atom or group -C-X; M represents nitrogen atom or group -C-X; Q represents nitrogen atom or group -C-X and wherein a ring comprises maximally one nitrogen atom; X represents hydrogen atom; W represents hydrogen or halogen atom; R1 represents aryl similarly or differently optionally mono- or multi-substituted with halogen atom, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl or group =O and wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 16 ring atoms and comprising in ring instead carbon one or more similar or different heteroatoms, such as oxygen, nitrogen or sulfur and it can be mono-, bi- or tricyclic and condensed additionally condensed with benzene ring; R2 and R3 represent independently of one another hydrogen atom or aryl similarly or differently mono- or multi-substituted with halogen atom, cyano-group, (C1-C6)-alkyl, phenyl, hydroxy-(C1-C6)-alkyl, halogen-(C1-C6)-alkyl or group -NR6R7, -OR5, (C1-C6)-alkyl-OR5-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkenyl wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms and comprising in ring instead carbon one or more heteroatoms, such as nitrogen or sulfur; or R2 and R3 in common with nitrogen atom form (C3-C8)-ring that can comprise optionally one more nitrogen or oxygen atom or it can comprise group -N(R10); R5 represents hydrogen atom; R6 and R7 represent independently of one another hydrogen atom or (C1-C6)-alkyl; R8 represents (C1-C6)-alkyl mono- or multi-substituted optionally with halogen atom or benzyl; R9 represents hydrogen atom or tri-(C1-C6)-alkylsilyl; R10 represents hydrogen atom or (C1-C6)-alkyl, and their isomers, enantiomers and salts also. Also, invention describes a medicinal agent based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 162 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of cyclic amine of the general formula (1): , their pharmaceutically acceptable salts or hydrates wherein each among R1, R2 and R3 represents independently hydrogen atom, halogen atom, hydroxy-group, (C1-C8)-alkoxy-group; each among W1 and W2 represents independently nitrogen atom (N) or -CH; X represents oxygen atom (O), -NR4, -COONR4 or -NR4CO; R4 represents hydrogen atom, (C1-C8)-alkyl, (C3-C6)-alkynyl, substituted or unsubstituted phenyl, unsubstituted benzyl, unsubstituted indanyl wherein substitute(s) of phenyl represent(s) 1-3 groups or atoms chosen from (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkoxy-group substituted with 1-3 halogen atoms, (C1-C8)-alkylthio-group, (C1-C8)-alkylsulfonyl, halogen atom, trifluoromethyl group and (C1-C3)-alkylenedioxy-group; each among l, m and n represents number 0 or 1. Proposed compounds possess inhibitory effect on cell adhesion and/or cell infiltration and can be used as a medicinal agent and pharmaceutical composition based on thereof.

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

6 cl, 1 tbl, 439 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula: or their pharmaceutically acceptable salts wherein Ra - R8a mean phenyl; R8b means pyridyl, or R8 means naphthyl; R1 means hydrogen atom; R2 - R9, R10, R11 mean substituted phenyl; R9, R10, R11 mean substituted pyridyl or pyrimidyl; R9, R10, R11 mean substituted pyridyl-N-oxide or pyrimidyl-N-oxide; R12, R13 mean substituted oxazolyl, naphthyl, fluorenyl, compounds of formulae , or ; R3 means hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl; R8 means phenyl; R8 means phenyl-(C1-C6)-alkyl, or R8 means thienyl-(C1-C6)-alkyl; R4, R5, R7 and R13 mean independently hydrogen atom or (C1-C6)-alkyl; R6 means hydrogen atom or (C1-C6)-alkyl; R8 means 1-3 substitutes that mean independently hydrogen atom, halogen atom, (C1-C6)-alkoxyl or -CF3; R8a means 1-3 substitutes that mean independently hydrogen atom, halogen atom, -CF3, -CF3O, -CN; R14 means phenyl, -NHCOCF3 and imidazolyl; R8b means 1-3 substitutes that mean independently hydrogen atom or halogen atom; R9 and R10 mean independently (C1-C6)-alkyl, halogen atom, -NR17R18, -OH, -CF3 and -OCH3; R11 means R9, hydrogen atom, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CN=NOR17, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, -N(R17)CONR18R19, -NHCONH-(chloro-(C1-C6)-alkyl), -NHCONH-((C3-C10)-cycloalkyl-(C1-C6)-alkyl), -NHCO-(C1-C6)-alkyl, -NHCOCF3, -NHSO2N-((C1-C6)-alkyl)2, -NHSO2-(C1-C6)-alkyl, -N(SO2CF3)2, -NHCO2-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, -SR20, -OSO2-(C1-C6)-alkyl, -SO2CF3, hydroxy-(C1-C6)-alkyl, -CONR17R18, -CON(CH2CH2-O-CH3)2, -OCONH-(C1-C6)-alkyl, -Si(CH3)3 or -B(OC(CH3)2)2; R12 means (C1-C)-alkyl or R14-phenyl; R14 means 1-3 substitutes that mean independently hydrogen, (C1-C6)-alkyl, -CF3, -CO2R17, -CN, (C1-C6)-alkoxyl and halogen atom; R15 and R16 mean independently hydrogen atom and (C1-C6)-alkyl, or R15 and R16 mean in common (C2-C5)-alkylene group and in common with carbon atom to which they are bound form (C3-C6)-spiran ring; R17, R18 and R19 mean independently hydrogen atom or (C1-C6)-alkyl; R20 means (C1-C6)-alkyl. Also, invention describes pharmaceutical compositions containing these compounds and using novel compounds as CCR5 antagonists in treatment of HIV infection, arthritis, asthma, cerebrospinal sclerosis and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

29 cl, 30 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

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

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes compound of the formula (I): wherein B represents oxygen atom (O) or -NR1; J represents 5-membered heteroaromatic ring representing group of the formula (J-1): optionally substituted with 1-2 radicals R5 wherein Q represents -NR5; each X, Y and Z represents independently nitrogen atom (N), -CH or - CR5; B1 represents O; R2 represents hydrogen atom (H) or (C1-C6)-alkyl optionally substituted with one halogen atom, or (C2-C6)-alkynyl; or R1 and R2 taken in common form a binding chain consisting of 2-3 members and comprising at least one carbon atom, optionally comprising one carbon atom as -C(=O), optionally substituted with R3 wherein R3 represents (C1-C2)-alkyl; each R represents independently H, (C1-C6)-alkyl, halogen atom or -CN; each R5 represents independently (C1-C6)-halogenalkyl or halogen atom, or each ring is substituted with one R6; each R6 represents independently halogen atom; n represents a whole number 1 or 2. Also, invention describes a composition used for control of insects and comprising the biologically effective dose of compound of the formula (I) and at least one additional component chosen from group comprising surface-active substances, solid and liquid diluting agents, and methods for control of insects with using compositions based on compounds of the formula (I) and compounds of the formula (I). Proposed compounds of the formula (I) possess insecticide activity and can be used in agriculture.

EFFECT: valuable insecticide properties of compounds and compositions.

11 cl, 26 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of quinoline of the formula (I): wherein R1 and R2 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, phenyl, unsubstituted benzyl or benzyl substituted with halogen atom, cyano-group, trifluoromethyl, alkyl, alkoxy-group, benzylcarbonyl, pyridinyl, furyl, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-, thiophenyl-SO2; or R1 and R2 in common with atom N to which they are added form piperidino-group, pyrrolidinyl, morpholinyl, azepanyl, 3,4-dihydro-1H-isoquinolinyl, and wherein heterocyclic ring is optionally substituted with one or some substitutes chosen independently from alkyl and alkoxy-group; R3 represents hydrogen atom, alkyl; R4 represents hydrogen atom; A in common with nitrogen atom that is added to quinoline ring represents pyrrolidinyl, azepanyl, and ring A is optionally substituted with one-three substitutes chosen independently from alkoxy-group, hydroxyalkyl, alkoxyalkyl. Also, invention describes methods of synthesis of quinoline derivatives of the formula (I). Proposed compounds can be used as components of pharmaceutical formulations in treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes mellitus, renal insufficiency, disorders in food eating and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 122 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

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

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula: or their pharmaceutically acceptable salts wherein Ra - R8a mean phenyl; R8b means pyridyl, or R8 means naphthyl; R1 means hydrogen atom; R2 - R9, R10, R11 mean substituted phenyl; R9, R10, R11 mean substituted pyridyl or pyrimidyl; R9, R10, R11 mean substituted pyridyl-N-oxide or pyrimidyl-N-oxide; R12, R13 mean substituted oxazolyl, naphthyl, fluorenyl, compounds of formulae , or ; R3 means hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl; R8 means phenyl; R8 means phenyl-(C1-C6)-alkyl, or R8 means thienyl-(C1-C6)-alkyl; R4, R5, R7 and R13 mean independently hydrogen atom or (C1-C6)-alkyl; R6 means hydrogen atom or (C1-C6)-alkyl; R8 means 1-3 substitutes that mean independently hydrogen atom, halogen atom, (C1-C6)-alkoxyl or -CF3; R8a means 1-3 substitutes that mean independently hydrogen atom, halogen atom, -CF3, -CF3O, -CN; R14 means phenyl, -NHCOCF3 and imidazolyl; R8b means 1-3 substitutes that mean independently hydrogen atom or halogen atom; R9 and R10 mean independently (C1-C6)-alkyl, halogen atom, -NR17R18, -OH, -CF3 and -OCH3; R11 means R9, hydrogen atom, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CN=NOR17, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, -N(R17)CONR18R19, -NHCONH-(chloro-(C1-C6)-alkyl), -NHCONH-((C3-C10)-cycloalkyl-(C1-C6)-alkyl), -NHCO-(C1-C6)-alkyl, -NHCOCF3, -NHSO2N-((C1-C6)-alkyl)2, -NHSO2-(C1-C6)-alkyl, -N(SO2CF3)2, -NHCO2-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, -SR20, -OSO2-(C1-C6)-alkyl, -SO2CF3, hydroxy-(C1-C6)-alkyl, -CONR17R18, -CON(CH2CH2-O-CH3)2, -OCONH-(C1-C6)-alkyl, -Si(CH3)3 or -B(OC(CH3)2)2; R12 means (C1-C)-alkyl or R14-phenyl; R14 means 1-3 substitutes that mean independently hydrogen, (C1-C6)-alkyl, -CF3, -CO2R17, -CN, (C1-C6)-alkoxyl and halogen atom; R15 and R16 mean independently hydrogen atom and (C1-C6)-alkyl, or R15 and R16 mean in common (C2-C5)-alkylene group and in common with carbon atom to which they are bound form (C3-C6)-spiran ring; R17, R18 and R19 mean independently hydrogen atom or (C1-C6)-alkyl; R20 means (C1-C6)-alkyl. Also, invention describes pharmaceutical compositions containing these compounds and using novel compounds as CCR5 antagonists in treatment of HIV infection, arthritis, asthma, cerebrospinal sclerosis and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

29 cl, 30 tbl, 31 ex

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