Derivatives of quinoline as npy antagonists

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

 

The present invention relates to new quinoline derivative, useful as ligands of the receptor for neuropeptide Y (NPY), particularly antagonists of neuropeptide Y (NPY).

The invention primarily relates to compounds of the formula

in which

R1and R2independently selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, aryl, aralkyl, arylcarbamoyl, aralkylamines, alkoxyalkyl, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, geterotsiklicheskikh, geterotsiklicheskikh, carboxanilide, carboxycellulose, amino, alkyl-SO2-, aryl-SO2-, heterocyclyl-SO2- or amino-SO2-, or R1and R2together with the N atom to which they are attached, form a 5 - to 10-membered heterocyclic ring, which optionally includes a second heteroatom selected from nitrogen or oxygen, and where the heterocyclic ring optionally substituted by one or more substituents, independently selected from alkyl and alkoxy;

R3represents hydrogen, alkyl, amino or halogen;

R4represents hydrogen, halogen, heterocyclyl, amino or alkyl;

Rather it represents a 5 to 7-membered saturated heterocyclic ring including the General nitrogen atom, which is attached to the quinoline ring and optionally a second heteroatom selected from oxygen, sulfur or nitrogen, where the ring And optionally substituted with one to three substituents, independently selected from alkyl, alkoxy, hydroxy, amino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, cycloalkylcarbonyl and cycloalkylcarbonyl;

and their pharmaceutically acceptable salts and esters.

The compounds of formula I and their pharmaceutically acceptable salts and esters are new and have valuable pharmacological properties. They are ligands for the neuropeptide, for example antagonists of neuropeptide receptor, and, in particular, they are selective antagonists of the receptor Y5 neuropeptides Y.

Neuropeptide Y is a peptide of 36 amino acids, which is widely distributed in the Central and peripheral nervous system. This peptide Mediaset many physiological actions through different receptor subtypes. Animal studies have shown that neuropeptide Y is a potent stimulator of food intake, and it has been shown that activation of the Y5 receptor neuropeptide Y leads to hyperphagia and reduced thermogenesis. Therefore, compounds that antagonizing neuropeptide Y receptor subtype Y5, provide an approach for the treatment of eating disorders, such as obesity and hiperf the Gia.

The currently used approach tends to medical intervention to promote weight loss or prevent weight gain. This is achieved through control of appetite, which is set by the hypothalamus, an important brain region, which, as proven controls food intake. It has been proven that neuropeptide Y (NPY) is one of the most powerful Central mediators of food intake in several animal species. Increased NPY levels lead to greater food consumption. It has been described that control appetite and increase weight to play the role of different receptors, neuropeptide Y (NPY). Intervention in these receptors, likely to reduce appetite and therefore will stop the weight gain. Reduction and long-term maintenance of body weight can also favorably influence the associated risk factors, such as arthritis, cardiovascular disease, diabetes and renal failure.

Accordingly, the compounds of formula I, their salts and esters can be used for prevention or treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.

Objects of the present invention are the compounds of formula I and their aforementioned salts and esters as such and their use as therapeutic the ski active substances, the method of obtaining these compounds, intermediate compounds, pharmaceutical compositions, drugs, containing these compounds, their pharmaceutically acceptable salts and esters, the application of the said 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 the application of the said compounds, salts and esters to obtain drugs for treatment or prevention of arthritis, cardiovascular diseases, diabetes, renal failure and particularly violations of the reception food and obesity.

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

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

The term "alkoxy", alone or in combination, signifies a group of the formula alkyl-O-, where the term "alkyl" has the previously mentioned meaning, 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", alone or in combination, signifies a phenyl or naftalina group, preferably the phenyl group, which optionally has one or more, especially one to three, substituents, each independently selected from halogen, trifloromethyl, amino, alkyl, alkoxy, aryloxy, alkylsulphonyl, cyano, carbamoyl, alkoxycarbonyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, hydroxy, nitro, etc. Preferred for estately aryl, preferably phenyl, independently selected from halogen, trifloromethyl, alkyl, alkoxy, cyano and nitro. Examples of aryl are phenyl, cyanophenyl, methoxyphenyl, forfinal and were.

The term "aralkyl", separately or in combination, signifies an alkyl or cycloalkyl group, as previously defined, which is substituted by one or more, preferably one or two, particularly preferably a single, aryl groups, and where the term aryl is defined above. Examples are benzyl, benzyl, substituted hydroxy, alkoxy or halogen, preferably fluorine.

The term "heterocyclyl", separately or in combination, denotes a saturated, partially unsaturated or aromatic 4 - to 10-membered heterocycle that contains one or more, preferably one or two heteroatoms selected from nitrogen, oxygen and sulphur, oxygen and especially nitrogen are preferred. If necessary, it can be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo, alkoxyalkyl, hydroxyalkyl, etc. 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-) hydroxy, halogen, alkyl, cycloalkyl and preferably alkoxy. Examples of such geterotsiklicheskikh are pyridinyl, furyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 3,4-dihydro-1H-ethenolysis, thiophenyl and azepane, where each of these rings may be optionally substituted by one or more, preferably one, substituents, independently selected from alkyl and halogen. Especially preferred is pyrrolidinyl, pyridinyl, furyl, thiophenyl and chloropyridinyl.

The term "carboxyllic", separately or in combination, refers to a partially unsaturated 4 - to 10-membered carbocyclic ring, where optionally one or more carbon atoms substituted with halogen, alkyl, cycloalkyl, alkoxy, oxo, aryl, preferably alkyl. Example carboxanilide is indanyl.

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

The term "cycloalkenyl", separately or in combination, the seat is tons alkyl group, which is substituted by one or more, preferably one, cycloalkenyl groups, and where the term alkyl and cycloalkyl have previously specified value.

The term "cycloalkylcarbonyl", separately or in combination, signifies a group of cycloalkenyl-C(O)-, where cycloalkenyl previously defined.

The term "cycloalkylcarbonyl", separately or in combination, refers to alkoxygroup, which is substituted by one or more, preferably one, cycloalkenyl groups, and where the terms alkoxy and cycloalkyl have previously specified value.

The term "cycloalkylcarbonyl", separately or in combination, refers to an alkyl group that is substituted by one or more, preferably one, cycloalkylcarbonyl, and where the terms alkyl, cycloalkylcarbonyl have previously specified value.

The term "geterotsiklicheskikh", separately or in combination, signifies a group of geterotsiklicheskikh-C(O)-, where geterotsiklicheskikh previously defined.

The term "aralkylamines", separately or in combination, signifies a group of aralkyl-C(O)-, where aralkyl previously defined.

The term "alkylaryl", separately or in combination, refers to the group alkyl-(CO)-, where the term alkyl has previously specified value.

The term "cycloalkylcarbonyl", separately or in combination, signifies a group of cycloalkyl-(CO)-, where the term of the CEC shall alkyl has previously specified value.

The term "arylcarbamoyl", separately or in combination, refers to the group aryl-(CO)-, where the term aryl is previously specified value.

The term "alkoxyalkyl", separately or in combination, refers to an alkyl group that is substituted by one or more, preferably one, alkoxygroup, and where the terms alkyl and alkoxy have previously specified value.

The term "hydroxyalkyl", separately or in combination, refers to an alkyl group that is substituted by one or more, preferably one, hydroxy groups, and where the terms alkyl and hydroxy have previously specified value.

The term "geterotsiklicheskikh", separately or in combination, refers to an alkyl group that is substituted by one or more, preferably one, heterocyclyl groups, and where the terms alkyl and heterocyclyl have previously specified value.

The term "heterocalixarenes", separately or in combination, refers to a group heterocyclyl-(CO)-, where the term heterocyclyl has previously specified value.

The term "carboxylicacid", separately or in combination, refers to an alkyl group that is substituted by one or more, preferably one, carboxylicacid groups, and where the terms alkyl and carboxyllic have previously specified value.

The term "halogen" denotes fluorine, chlorine, bromine or iodine, prepact the positive fluorine, chlorine or bromine and especially chlorine.

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

The term "nitro", separately or in combination, signifies a group-NO2.

The term "hydroxy", separately or in combination, refers to a group-IT.

The term "carbonyl" refers to a group of the formula-C(O)-.

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 with organic acids, such as methanesulfonate acid, formic acid, acetic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, salicylic acid and oxalic acid. Preferred are cleaners containing hydrochloride salt. The compounds of formula I with free carboxyglutamic can also form salts with physiologically compatible bases. Examples of such salts are salts with alkali metals, alkaline earth metals, ammonium and alkylammonium salts such as Na, K, CA, or Tetramethylammonium salt. The compound of the formula I can also be present in the form zwitterions.

The compounds of formula I can also be in the form of a solvate such as a hydrate. Solvation can be made is during the way obtaining or may occur for example, as a consequence of hygroscopic properties initially anhydrous compound of formula I (hydration). The term pharmaceutically acceptable salts also includes pharmaceutical suitable solvate.

The term pharmaceutically acceptable esters of compounds of formula I indicates that the compounds of General formula (I) can be derivationally functional groups to obtain derivatives that can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically unstable ether derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of General formula (I), like metabolically unstable esters, which are capable of forming starting compound of General formula (I) in vivo, are included in the scope of this invention.

In more detail, for example, the COOH group of compounds according to formula I can be tarifitsirovana. Alkyl and kalkilya esters are examples of suitable esters. Methyl, ethyl, propyl, butyl and benzyl esters are the preferred esters. Methyl and ethyl esters are particularly preferred. Further examples of suitable pharmaceutical ether which are the compounds of formula I, where the hydroxy-group can be tarifitsirovana. Examples of such esters are the format, acetate, propionate, butyrate, isobutyrate, valeriat, 2-methylbutyrate, isovaleric 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 action of lipases, such as gastric and pancreatic lipases. For example, orlistat and lipstatin, as described in US 4598089, are strong inhibitors of lipases. Lipstatin is a natural product of microbial origin, and orlistat is the result of hydrogenation of lipstatin. Another inhibitor of lipases includes a class of compounds commonly referred to as anglicani. Anglicani are analogues of orlistat (Mutoh and others, 1994). The term "lipase inhibitor" refers to a polymeric binding of lipase inhibitors, for example, described in WO 99/34786 (Geltex Pharmaceuticals Inc). These polymers are characterized by the fact that they have been replaced by one or more groups which inhibit the lipase. The term "lipase inhibitor" also includes pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" preferably refers to orlistat.

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

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

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

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

In the description used in this application, the ring atoms of the quinoline ring are numbered as follows:

where R3attached in 2-position and R4attached at the 6 position.

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

Further preferred are the compounds of formula I in which R1and R2independently selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkylcarboxylic, cycloalkylcarbonyl, aryl, aralkyl, arylcarbamoyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, geterotsiklicheskikh, geterotsiklicheskikh, carboxanilide, carboxycellulose, amino, alkyl-SO2-, aryl-SO2-, heterocyclyl-SO2- or amino-SO2or R1and R2together with the N atom to which they are attached, form a 5 - to 10-membered heterocyclic ring, which optionally includes a second heteroatom selected from nitrogen or oxygen, and where the heterocyclic ring optionally substituted by one or more substituents, independently selected from alkyl and alkoxy; and

Rather it represents a 5 to 7-membered saturated heterocyclic ring including the nitrogen atom attached to the ring ginoli is a, and optionally a second heteroatom selected from oxygen, sulfur or nitrogen, where the ring is optionally substituted with one to three substituents, independently selected from alkyl, alkoxy, hydroxy, amino, acetylamino, cyano, hydroxyalkyl and alkoxyalkyl.

Preferred are compounds according to formula I, in which R3represents hydrogen or alkyl. Preferred are the compounds of formula I in which R3represents hydrogen. Further preferred compounds are compounds in which R3represents alkyl. Especially preferred are the compounds of formula I in which R3represents methyl.

Also preferred are the compounds of formula I in which R4represents hydrogen or alkyl. Further preferred are the compounds of formula I in which R4represents hydrogen or methyl. Especially preferred are compounds according to formula I, in which R4represents hydrogen.

Another preferred embodiment of the present invention are compounds according to formula I, in which R4represents amino, especially pyrrolidinyl.

Also preferred are compounds according to formula I, in which the s And represents pyrrolidin or ASEAN, optionally substituted by alkyl, alkoxyalkyl or hydroxyalkyl. Especially preferred are the compounds of formula I in which a represents pyrrolidine, optionally substituted by hydroxymethyl or methoxymethyl.

Preferred are the compounds of formula I in which a represents pyrrolidin or ASEAN, optionally substituted alkyl, alkoxyalkyl, hydroxyalkyl or alkoxy.

Further preferred are compounds according to formula I in which a represents pyrrolidin or ASEAN, optionally substituted by alkyl, alkoxy, alkoxyalkyl or hydroxyalkyl. Especially preferred are the compounds of formula I in which a represents pyrrolidine, optionally substituted by hydroxymethyl, methoxymethyl, methoxy or ethoxy.

Another preferred embodiment implementation of the present invention are compounds according to formula I, in which one of R1and R2represents hydrogen or alkyl and the other is independently selected from alkyl, cycloalkyl, cycloalkenyl, alkylcarboxylic, cycloalkylcarbonyl, phenyl, naphthyl, phenylalkyl, naphtylamine, phenylcarbinol, alkoxyalkyl, hydroxyalkyl, thiophenyl, pyridinyl, furil, thiophenolate, peridiniella, farilalilla, Tifani is carbonyl, pyridylcarbonyl, farilalilla, indanyl, carboxycellulose, amino, alkyl-SO2-, aryl-SO2-thiophenyl-SO2-, pyridinyl-SO2-, furyl-SO2- or amino-SO2-and where phenyl and raftiline group optionally substituted by one to three substituents, independently selected from alkyl, cyano, halogen, alkoxy and trifloromethyl,

or R1and R2together with the N atom to which they are attached, form asianave, 3,4-dihydro-1H-isoquinoline, piperidine, pyrolidine or morpholine ring, which is optionally substituted with one to three substituents, independently selected from alkyl and alkoxy.

Preferred are the compounds of formula I in which one of R1and R2represents hydrogen or methyl and the other is independently selected from alkylcarboxylic, cycloalkylcarbonyl, cyanophenyl, alkoxybenzyl, cyanovinylene, florfenicol, thiophenolate, pyridylcarbonyl, fullcarbon, alkyl-SO2-, pyridyl-SO2pyridinyl and cycloalkylcarbonyl.

Especially preferred embodiment implementation of the present invention are the compounds of formula I in which one of R1and R2represents hydrogen or methyl and the other is independently selected from alkylcarboxylic, cycloalkylcarbonyl, cyano phenyl, alkoxybenzyl, tzia is openinterval, florfenicol, thiophenolate, pyridylcarbonyl, fullcarbon, alkyl-SO2- and pyridyl-SO2-.

Preferred are the compounds of formula I in which one of R1and R2represents hydrogen. Especially preferred are compounds in which one of R1and R2represents hydrogen and the other is other than hydrogen Deputy.

Examples of preferred compounds of the formula I:

1. (R)-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]propionamide;

2. (2-methoxyethyl)methyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

3. (R)-cyclopropylmethyl-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amine;

4. (R,S)-cyclopropylmethyl-[2-methyl-4-(2-methylpyrrolidine-1-yl)quinoline-7-yl]amine;

5. (S)-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]-2,2-dimethylpropanamide;

6. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide cyclopropanecarbonyl acids;

7. cyclopropylmethyl-(4-pyrrolidin-1-rhinolin-7-yl)amine;

8. 2,2-dimethyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide;

9. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide cyclobutanecarbonyl acids;

10. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-3-ylamine;

11. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)phenylamine;

12. 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylamino)benzonitrile;

13. N-(2-methyl-4-pyrrolidin-1-ilhi the Olin-7-yl)propionamide;

14. 3-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)butyramide;

15. (2-methoxyethyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

16. isobutyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

17. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide, furan-2-carboxylic acid;

18. N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)nicotinamide;

19. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-(2-trifloromethyl)amine;

20. (2,3-dimethylbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

21. [2-(2-chlorophenyl)ethyl]-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

22. cyclopropylmethyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

23. (2.2-dimethylpropyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

24. indan-1-yl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

25. methyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)phenylamine;

26. 4-[(2-methyl-4-pyrrolidin-1-rhinolin-7-ylamino)methyl]benzonitrile;

27. (4-terbisil)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

28. 4-cyano-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide;

29. (2-methoxybenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)Amin

30. (2,6-diferensial)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

31. benzhydryl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

32. ethyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-4-ylmethylamino;

33. furan-2-ylmethyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

34. (2-methyl-4-pyrrolidin-1-rhinolin-7-is)thiophene-2-ylmethylamino;

35. 7-azepin-1-yl-2-methyl-4-pyrrolidin-1-rhinolin;

36. 2-fluoro-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide;

37. 4-methoxy-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide;

38. 4-fluoro-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide;

39. N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)isonicotinamide;

40. (4-azepin-1-yl-2-methylinosine-7-yl)-(4-trifloromethyl)amine;

41. (2-methylbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

42. (3,5-dimethylbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

43. (4-azepin-1-yl-2-methylinosine-7-yl)pyridine-3-ylmethylamino;

44. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-naphthalene-1-ylmethyl-amine;

45. [1-(4-chlorophenyl)ethyl]-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

46. the hydrochloride of N-(2-methyl-4,6-dipyrrole-1-rhinolin-7-yl)ndimethylacetamide;

47. hydrochloride of 2-methyl-4,6-dipyrrole-1-rhinolin-7-ylamine;

48. (4-methylamines)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

49. methyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-3-ylmethylamino;

50. (3-methoxybenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

51. (2,4-diferensial)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

52. (4-methoxybenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

53. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-4-ylmethylamino;

54. 7-(3,4-dihydro-1H-isoquinoline-2-yl)-2-methyl-4-pyrrolidin-1-rhinolin;

55. (2-methyl-4-pyrrolidin-1-rhinolin-yl)-(4-trifloromethyl)amine;

56. (2 chlorbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

57. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-3-ylmethylamino;

58. (4-chlorbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

59. 2-methyl-7-piperidine-1-yl-4-pyrrolidin-1-rhinolin;

60. 2-methyl-4,7-dipyrrole-1-rhinolin;

61. 2-methyl-7-morpholine-4-yl-4-pyrrolidin-1-rhinolin;

62. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-(3-methylthiophene-2-ylmethyl)amine;

63. (S)-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]nicotinamide;

64. N-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)nicotinamide;

65. [4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-furan-2-carboxylic acid;

66. N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanesulfonamide;

67. 4-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzosulfimide;

68. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide pyridine-3-sulfonic acid;

69. (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide 5-chlorothiophene-2-sulfonic acid;

70. N-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzosulfimide,

71. (2-chloropyridin-3-yl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

72. (R)-4-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

73. (R)-4-cyano-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]benzamide;

74. (R)-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]ndimethylacetamide;

75. (R)-4-fluoro-N-[4-(2-who ethoxymethylene-1-yl)-2-methylinosine-7-yl]benzamide;

76. (S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

77. (S)-{1-[2-methyl-7-(pyridine-3-ylamino)quinoline-4-yl]pyrrolidin-2-yl} methanol;

78. [4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-furan-2-carboxylic acid;

79. (S)-{1-[7-(2-chloropyridin-3-ylamino)-2-methylinosine-4-yl]pyrrolidin-2-yl}methanol;

80. [4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-cyclopropanecarbonyl acids;

81. (S)-4-cyano-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide;

82. (S)-4-fluoro-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide;

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

84. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]nicotinamide;

85. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]propionamide;

86. (S)-4-cyano-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide;

87. [4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-cyclopropanecarbonyl acids;

88. [4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-furan-2-carboxylic acid;

89. (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

90. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl] nicotinamide;

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

92. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]propionate is;

93. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-4-perbenzoic;

94. (S)-4-cyano-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide;

95. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-2,2-dimethylpropanamide;

96. (S)-2-(4-chlorophenyl)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]ndimethylacetamide;

97. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-2-pyridine-2-ylacetamide;

98. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-2-(4-methoxyphenyl)ndimethylacetamide;

99. (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-2-(3-triptoreline)ndimethylacetamide;

100. (S)-4-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

101. (S)-(4-forfinal)-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amine;

102. (S)-4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]pyridine-3-ylamine;

103. [4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amide(S)-cyclopropanecarbonyl acids;

104. (S)-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]-2,2-dimethylpropanamide;

105. (S)-cyclopropylmethyl-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amine;

106. (S)-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]propionamide;

107. (S)-4-cyano-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]benzamide;

108. (S)-[4-(2-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-(4-forfinal)amine;

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

110. [4-(2-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]amide(S)-furan-2-carboxylic acid;

111. (R/S)-4-[4-(2-methylpyrrolidine-1-yl)quinoline-7-ylamino]benzonitrile;

112. (S)-4-[4-(2-cyclopropanecarbonitrile-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

113. (S)-[4-(2-cyclopropanecarbonitrile-1-yl)-2-methylinosine-7-yl]pyridine-3-ylamine;

114. (R)-4-cyano-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide;

115. (S)-N-[4-(3-cyclopropylmethoxy-1-yl)-2-methylinosine-7-yl]nicotinamide;

116. (2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)amide, furan-2-carboxylic acid;

117. N-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide.

Examples of especially preferred compounds of formula I are

(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide cyclopropanecarbonyl acids;

2,2-dimethyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide;

4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylamino)benzonitrile;

3-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)butyramide;

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

N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)nicotinamide;

(2.2-dimethylpropyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

4-cyano-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide;

(2-methoxybenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)thiophene-2-Iletisim is n;

4-fluoro-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide;

N-(2-methyl-4-pyrrolidin-l-rhinolin-7-yl)isonicotinamide;

(S)-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl] nicotinamide;

N-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)nicotinamide;

[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]amide(S)-furan-2-carboxylic acid;

N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanesulfonamide;

(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide pyridine-3-sulfonic acid;

(R)-4-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

(S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

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

[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]amide(S)-cyclopropanecarbonyl acids;

(S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

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

(S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]propionamide;

[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amide (S)-cyclopropanecarbonyl acids;

(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)amide, furan-2-carboxylic acid;

N-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide.

Methods for obtaining compounds of formula I are also objects of the invention.

Use the on going further in the description of the ways in which the substituents and indices have the above significance, if not marked otherwise.

Compounds of General formula I can be obtained according to scheme 1 from compounds of formula Ia (Hal denotes Cl, Br or I), including the substituents R3and R4and in accordance with the above definitions, the reaction clutch, Pd catalyzed, in terms of Buchwald from the corresponding amines or amides of sulfonamides using, for example, Pd(OAc)2as the catalyst, BINAP (2,2-bis(diphenylphosphino)-1,1-dinaphthyl) or Xanthos as a chelating phosphine ligand, or with other palladium catalysts, such as SK-CC01-A (produced by Solvias), and NaOtBu or cesium carbonate as the base, in a solvent such as toluene or dioxane, and at elevated temperature (S.L.Buchwald in: J. Chem. Soc. 1996, R, Acc. Chem Res. 1998, p 805, Org Lett., 2000, 2, 1104).

Alternatively, binding can be performed using the Ullman reaction, for example, chloride Cu (I) or iodide Cu (I) in a solvent such as dioxane or DMF, by analogy with the methods described J.A.Ragan (1998 Synthesis, p 1599) and later S.L.Buchwald (J.Chem. Soc., 2001, 7727).

Scheme 1

Alternatively, the compounds of formula I can be obtained from the Ib in accordance with scheme 2, a suitable sequence of reactions alkylation with the appropriate alkylhalogenide in the presence of a base such as sodium hydride in T is f or DMSO, or using the Pd of Buchwald catalyzing the reaction of formation of communication C/N / bind Ullman, such as binding to aryl - and heteroarylboronic, as described above, when R1, R2represent aryl and heteroaryl). Compounds in which R1, R2are alkylsulphonyl, arylcarbamoyl, geterotsiklicheskikh, heteroaryl - or alkylsulfonyl, can be obtained from Ib using the acylation reaction (or sulfating) from the corresponding allelochemical or sulphonylchloride in the presence of a base, such as DMAP the triethylamine and in a solvent such as THF or DMF or methylene chloride. Hal in scheme 2 represents a chlorine, bromine or iodine.

Scheme 2

The following variant of the invention consists in the availability of appropriate substituents that are already included in the method of producing compounds of formula I in accordance with the scheme below.

Compounds with R4having above a certain value, can be obtained from 1C (scheme 3) binding of Buchwald catalyzed by Pd (from the corresponding amines or N-heterocycles), or R4-M (M represents Sn(Bu)3or IN(OH)2or salts of Li and Mg) cross-linking by Steele, Suzuki or Negishi, essentially known from the prior art, or R4already included in the way in with the accordance with the following reaction sequences.

Scheme 3

Alternatively, the substituents R4(heterocyclyl, amino) may be entered in accordance with scheme 4 the reaction of compounds of formula Id with an appropriate amine or N-heterocycle and in a suitable solvent, such as THF or DMSO (Hal denotes F, Cl, Br or I), or by using the above forming the connection of the reaction catalyzed by Pd, with getting Ie (Hal denotes Cl, Br or I). The transformation in Ie Ib carried out the restoration, for example, using SnCl2as a recovery agent, known from the prior art. Alternative sequence consists of converting the Id in the If, for example, a restore using SnCl2with the subsequent reaction of cross-linking catalyzed by palladium, as described above.

Scheme 4

Compounds of General formula Ia-f can be obtained as follows.

The formation of compounds in accordance with formula Ia1, where R3represents hydrogen or alkyl, is carried out in accordance with scheme 5 starting from the corresponding anilines IIIa, which are known from the prior art or which can be obtained in accordance with standard procedures known from the prior art. Thus, condensation with the appropriate alkoxycarbonylmethyl Il the aldehydes in the presence of p-toluensulfonate acid by boiling under reflux in cyclohexane and in dry conditions, produced during the reaction, results derived enamine of General formula IV. Subsequent ring closure is achieved by heating at 250°in the high-boiling solvent, such as Dowtherm And obtaining compounds of General formula V. the Conversion of a derivative chlorhydrin formula VI is performed by processing POCl3while boiling under reflux, in a standard way known from the prior art. Subsequent reaction with the corresponding amines, as defined above, with the use of a large excess of amine without solvent or by reaction with 2-fold excess in a suitable solvent, such as N-organic, xylene, ethanol or THF, optionally in the presence of catalytic amounts of NaI and with pyridine as a base leads to the formation of compounds of formula A.

Scheme 5

R3represents hydrogen or alkyl;

R4represents methyl or ethyl.

Connection Ib1-If1 can be obtained in accordance with scheme 6, from correspondingly substituted anilines of the formula IIIb-f corresponding transformations applied according to the scheme 5.

Scheme 6

IIIb: R' represents NH2; R4defined above;

IIIc: R' represents NR1, R 2, R4represents Hal;

IIId: R' represents NO2, R4represents Hal;

IIIe: R' represents NO2, R4defined above;

IIIf: R' represents NH2, R4represents Hal.

The compounds of formula Ia2, in which R represents NH2alkylamino, dialkylamino or chlorine, can be obtained in accordance with scheme 7 from anilines of formula IIIa condensation allylcarbamate, the closure ring and the subsequent transformations of functional groups, as described above. The compounds with R3alkylamino or dialkylamino can be obtained, for example, from the intermediate compound VIII or Ia2 (R3represents NH2) selective N-alkylation. Compounds with R3denoting Cl, can be obtained from Ia2 (R3represents NH2) diazonium and reaction Sandmeyer with CuCl2.

Scheme 7

R3represents NH2alkylamino or dialkylamino;

R' represents methyl or ethyl.

By analogy to the sequence described in scheme 7, and from the corresponding anilines of formula IIIb-f, can be obtained from compounds of formula Ib2-If2 (R3represents NH2or alkylamino, or dialkylamino, or chlorine).

Following the procedure of obtaining compounds of General formula I includes condensation of anilines of formula IIIa with malonic esters to obtain compounds of formula IX. Subsequent ring closure leads to the production of 2,4-dihydroxyquinoline General formula X. Subsequent chlorination with POCl3results of 2,4-dechlorinating formula XI, which can be selectively converted into compounds A sequential substitution reactions with the corresponding amines by analogy with the reactions, known from the prior art. Connection Ib2-If2 can be obtained respectively from IIIb-f, as described above.

Scheme 8

R3represents NH2alkylamino, dialkylamino or chlorine,

R', R" represents methyl or ethyl.

The preferred methods are the ways in accordance with schemes 1, 2, 3, and 5.

The conversion of compounds of formula I in a pharmaceutically acceptable salt can be carried out by treatment of such compounds, inorganic acid, for example, halogenation acid, such as, for example, hydrochloric acid or Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate acid.

The conversion of compounds of formula I in a suitable pharmaceutically esters or amides can the be for example, treatment with a suitable present in the molecules of amino or hydroxyl groups of carboxylic acid, such as acetic acid with a condensing agent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexaflurophosphate (THIEF) or N,N-dicyclohexylcarbodiimide (DCC), resulting in receipt of ether carboxylic acids or carboxylic acid amide.

Preferred intermediate compounds are

a) 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin;

b) (R)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine;

C) 7-iodine-4-pyrrolidin-1-rhinolin;

g) 4-azepin-1-yl-7-iodine-2-methylinosine;

d) (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol;

(e) (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride;

W) (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine;

C) (S)-4-(2-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride;

and) (S)-4-(2-cyclopropanecarbonitrile-1-yl)-7-iodine-2-methylinosine hydrochloride;

K) (R)-1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-3-ol;

l) (R)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride;

m) (S)-1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-3-ol;

n) (S)-4-(3-cyclopropylmethoxy-1-yl)-7-iodine-2-methylinosine;

o) 7-iodine-2,6-dimethyl-4-pyrrolidin-1-rhinolin.

The next object of the invention are the above compounds of formula Dla use as therapeutically active substances.

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

Similarly, the object of the present invention are pharmaceutical compositions comprising the above compound of formula I and a therapeutically inert carrier.

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

The following object of the invention includes compounds that are received in accordance with one of the above methods.

The next 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, in which an effective amount of the above compounds.

In accordance with the following embodiment of the invention provides the manual for the treatment of obesity in humans, in need of such treatment, which comprises administration to a human a therapeutically effective amount of a compound according to formula I and a therapeutically effective amount of a lipase inhibitor, particularly preferably, in which the lipase inhibitor is a orlistat. It is also an object of the present invention is the above-mentioned method, in which the introduction is carried out simultaneously, separately or sequentially.

As a preferred embodiment of the present invention is the use of compounds of formula I for the manufacture of a medicine for the treatment and prevention of obesity in a patient who also takes a lipase inhibitor, particularly preferably, in which the lipase inhibitor is a orlistat.

The preferred method of obtaining compounds in accordance with formula I includes one of the following reactions:

a) Reaction of a compound in accordance with formula Ia in the presence of the compounds of formula XII with obtaining the compounds of formula I,

where R1-R4and As defined above and Hal denotes chlorine, bromine or iodine. In a preferred aspect of this reaction is the binding reaction catalyzed by Pd, in terms of Buchwald. Alternative preferred is the above-mentioned reaction is the presence of salts of Cu (I), preferably chloride Cu (I) or iodide Cu (I).

b) Reaction of the compound in accordance with formula Ib in the presence of one or both compounds of the formula R1-Hal and R2-Hal obtaining the compounds of formula I

where R1-R4and As defined above and Hal denotes chlorine, bromine or iodine.

C) reaction of the compound according to formula Ic in the presence of at least one of the following compounds selected from R4-Hal, R4Sn(Bu)3, R4B(OH)2, LiR4and HalMgR4preferably R4-Hal, R4Sn(Bu)3, R4B(OH)2with obtaining the compounds of formula I

where R1-R4and As defined in paragraph 1 and Hal represents chlorine, bromine or iodine.

The above-described compounds of formula I for use as therapeutically active substances are the following object of the invention.

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

Similarly, the object from which retene is a pharmaceutical composition, including the above compound of formula I and a therapeutically inert excipient. Preferred is a composition including a therapeutically effective amount of a lipase inhibitor. Especially preferred is the above composition, in which the lipase inhibitor is a orlistat.

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

The following object of the invention includes compounds that are received in accordance with one of the above methods.

The next 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, in which an effective amount of the above compounds.

In accordance with the following aspect of the invention provides a method of treating obesity in a human in need of such treatment, which comprises administration to a human a therapeutically effective amount of a compound according to formula I and a therapeutically effective amount of a lipase inhibitor, particularly is preferably about, in which the lipase inhibitor is a orlistat. Also the subject of the present invention is the above-mentioned method, in which the introduction is carried out simultaneously, separately or sequentially.

As a preferred embodiment of the present invention is the use of compounds of formula I for the manufacture of a medicine for the treatment and prevention of obesity in a patient who also takes a lipase inhibitor, particularly preferably, in which the lipase inhibitor is a orlistat.

Test methods

Cloning of cDNA NPY5 receptor mouse:

Full length cDNA encoding the NPY5 receptor mouse (mNPY5), amplified from cDNA of mouse brain using specific primers derived from the published sequence, and Pfu DNA polymerase (Stratagene). The amplification product was subcloned into the expression vector pcDNA3 mammalian using Eco RI and XhoI restriction sites. Positive clones sequenced, and selected a single clone that encodes the published sequence for the generation of stable cell clones.

Stable transfection:

Cells of the embryo kidney 293 people (NEC) (ATSS No. CRL-1573) were transferrable with 10 µg mNPY5 DNA using the reagent lipofectamine (Gibco BRL) according to the manufacturer's instructions. Two days after the tra is speccie initiated selection of geneticin (1 mg/ml), and provided several stable clones. One clone was then used for pharmacological characteristics.

Competitive binding radioligand:

Embryo cells of human kidney 293 (NEC)expressing recombinant NY5-receptor mouse (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 72,000× within 15 minutes the Residue was washed twice with 75 mm Tris buffer, pH 7.4, containing 25 mm MgCl2and 250 mm sucrose, 0.1 mm of phenylmethylsulfonyl and 0.1 mm 1,10-phenanthrolin, re-suspended in the same buffer and stored in aliquot at -80°C. Protein was determined in accordance with the method of Lowry using bovine serum albumin (BSA) as standard.

The test is a competitive binding radioligand were 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% NaN3containing 5 μg of protein, 100 PM [125I] labeled peptide YY (PYY) and 10 μl of DMSO containing high amount of unlabeled test compounds. After incubation for 1 h at 22°bound peroxidase and free ligand were separated by filtration on filters fiberglass. Nonspecific binding was assessed in the presence of 1 μm unlabeled PYY. Specific binding was defined as the difference between total binding is nonspecific binding. The values of the IC50was defined as the concentration of antagonist, which is 50% replaces the binding of labeled [125I] neuropeptide Y. It was determined by linear regression analysis after transformation logit/log data binding.

The results obtained in the previous test from illustrating compounds of the invention as the test compounds shown in the following table:

ConnectionIC50
Example 20.7 nm
Example 540.3 nm

Described above, preferred compounds have the meanings IC50below 1000 nm; more preferred compounds are the values of the IC50below 100 nm, especially below 10 nm. The most preferred compounds are the values of the IC50below 1 nm. These results were obtained using the previous test.

The compounds of formula I and their suitable pharmaceutically salt, solvate and esters can be used as drugs (e.g., in the form of pharmaceutical compositions). The pharmaceutical compositions can be administered orally, for example, orally (for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasal (e.g., in the form of WHI is lnyh sprays) or rectally (e.g., in the form of suppositories). However, the introduction may also be administered parenterally, e.g. intramuscularly, or intravenously (for example, in the form of solutions for injection).

The compounds of formula I and their pharmaceutically suitable salts, solvate and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants to obtain tablets, coated tablets, dragées and hard gelatin capsules. Can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., for example, as adjuvants for tablets, coated tablets and hard gelatin capsules.

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

Suitable adjuvants for obtaining solutions and syrups are, for example, water, polyols, sucrose, inverted sugar, glucose, etc.

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

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

In addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, substances to increase Vascos and, stabilizers, moisturizing agents, emulsification, sweeteners, colorants, odorants, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically active substances.

In accordance with the invention the compounds of formula I and their pharmaceutically suitable salts, solvate and ethers can be used for the prevention and treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity. The dosage may vary within wide limits and will, of course, depend on the individual requirements in each particular case. Usually, in the case of oral administration a daily dosage is from about 0.1 mg to 20 mg per kg body weight, preferably from about 0.5 mg to 4 mg per kg of body weight (for example, approximately 300 mg per person), preferably separated by 1-3 individual doses, which may contain, for example, equal quantities. However, it is clear that the upper limit specified above may be exceeded if necessary.

The invention is illustrated by the following examples which are not intended to limit.

Examples

Example 1

a) a Suspension of 1.01 g (3 mmol) of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin, 0,186 g (0.3 mmol) of rac BINAP, or 33.7 mg (0.5 mmol) of palladium (II) acetate and 0.87 g (9 mmol) of tert-butyl sodium in toluene (25 ml) was treated at room temperature 0,427 g (6 mmol) of aminomethylpropanol and then was heated by boiling under reflux in an atmosphere of argon for 20 hours, the Reaction mixture was then filtered by suction on a glass fiber filter and the filtrate was separated between EtOAc and water. The layers were separated, the organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was applied onto a column of silica gel with CH2Cl2/MeOH/NH4OH (15:1:0,2) as eluent. The Association of the purified fractions and evaporation in vacuum resulted in the receipt of 253 mg (30%) of the desired cyclopropylmethyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a pale yellow foam. ISP mass spectrum, m/e: 282,2 (M+1 calculated for C18H23N3O: 282).

Obtaining input data:

b) a Suspension of 2 g (6,59 mmol) 4-chloro-7-iodine-2-methylinosine (EP 497371) in ethanol (20 ml) was treated sequentially 1.28 g (18.0 mmol) of pyrrolidine, pyridine (0.2 ml) and 50 mg (0.3 mmol) of potassium iodide and the resulting mixture was boiled under reflux for 24 hours After evaporation in vacuo the residue was transferred into water (50 ml) and podslushivaet to pH 12 by the introduction of a 2 M aqueous solution of sodium hydroxide. The precipitate was collected by filtration, washed with water (20 ml) and ether (20 ml) and dried under vacuum to obtain 1,95 g (87%) 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin in the form of a nearly white solid, tPL99-102°C.

Example 2

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin from what butylamine was obtained isobutyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as an almost white solid. ISP mass spectrum, m/e: 284,2 (M+1 calculated for C18H25N3:284).

Example 3

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2,2-dimethylpropanamide was obtained (2,2-dimethylpropyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a brown foam. ISP mass spectrum, m/e: 298,4 (M+1 calculated for C19H27N3: 298).

Example 4

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2 methoxyethylamine was obtained (2-methoxyethyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a brown foam. ISP mass spectrum, m/e: of 286.2 (M+1 calculated for C17H23N3About: 286).

Example 5

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with N-(2-methoxyethyl)methylamine was obtained (2-methoxyethyl)methyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine in the form of an amorphous brown solid. ISP mass spectrum, m/e: 300,4 (M+1 calculated for C19H25N3A: 300).

Example 6

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with piperidine was obtained 2-methyl-7-piperidine-1-yl-4-pyrrolidin-1-rhinolin in the form of a brown viscous oil. ISP mass spectrum, m/e: usd296.4 (M+1 calculated for C19H25N3: 296).

Example 7

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with Pyrrhus what Ledeen was obtained 2-methyl-4,7-dipyrrole-1-rhinolin in the form of a brown viscous oil. ISP mass spectrum, m/e: 282,2 (M+1 calculated for C18H23N3: 282).

Example 8

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with morpholine was obtained 2-methyl-7-morpholine-4-yl-4-pyrrolidin-1-rhinolin in the form of a brown viscous oil. ISP mass spectrum, m/e: 298,4 (M+1 calculated for C18H23N3O: 298).

Example 9

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with hexamethylenimine was obtained 7-azepin-1-yl-2-methyl-4-pyrrolidin-1-rhinolin in the form of a brown viscous oil. ISP mass spectrum, m/e: 310,3 (M+1 calculated for C20H27N3: 310).

Example 10

(a) By analogy with example 1A), by the reaction of (R)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine with cyclopropanemethylamine was obtained (R)-cyclopropylmethyl-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amine as brown amorphous solid. ISP mass spectrum, m/e: 326,4 (M+1 calculated for C20H27N3O: 326).

Obtaining input data:

b) In analogy with example 1B), on reaction of 4-chloro-7-iodine-2-methylinosine with (R)-2-(methoxymethyl)pyrrolidine (commercially available) was obtained (R)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine in the form of a nearly white solid, tPL61-64°C.

Example 11

(a) By analogy with example 1A), by the reaction of (R,S)-7-yo is-2-methyl-4-(2-methylpyrrolidine-1-yl)quinoline with cyclopropanemethylamine was obtained (R,S)-cyclopropylmethyl-[2-methyl-4-(2-methylpyrrolidine-1-yl)quinoline-7-yl]amine as brown amorphous solid. ISP mass spectrum, m/e: 396,4 (M+1 calculated for C19H25N3: 296).

Obtaining input data:

b) In analogy with example 1B), on reaction of 4-chloro-7-iodine-2-methylinosine with (R,S)-(2-methyl)pyrrolidine (commercially available) was obtained (R,S)-7-iodine-2-methyl-4-(2-methylpyrrolidine-1-yl)quinoline as a light brown solid, tPL36-40°C.

Example 12

(a) By analogy with example 1A), by the reaction of 7-iodine-4-pyrrolidin-1-rhinolin with cyclopropanemethylamine was obtained cyclopropylmethyl-(4-pyrrolidin-1-rhinolin-7-yl)amine as a viscous oil. ISP mass spectrum, m/e: 268,4 (M+1 calculated for C17H21N3: 268).

Obtaining source material

b) In analogy with example 1B), on reaction of 4-chloro-7-athineon (receive: Surrey, and other, JACS, 68, R, 1946) pyrrolidine was obtained 7-iodine-4-pyrrolidin-1-rhinolin in the form of a light brown solid. ISP mass spectrum, m/e: 325,2 (M+1 calculated for C13H13N3: 325).

Example 13

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 3-aminopyridine was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-3-ylamine as a brown solid. ISP mass spectrum, m/e: 305,3 (M+1 calculated for C19H20N4: 305).

Example 14

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with an who Lin was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)phenyl-3-ylamine as a brown solid. ISP mass spectrum, m/e: 304,3 (M+1 calculated for C20H21N3: 304).

Example 15

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-aminobenzonitrile was obtained 4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylamino)benzonitrile in the form of a light brown solid. ISP mass spectrum, m/e: 329,4 (M+1 calculated for C21H20N4: 329).

Example 16

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2 triphtalocyaninine was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-(2-trifloromethyl)amine as light brown foam. ISP mass spectrum, m/e: 386,3 (M+1 calculated for C22H22F3N3: 386).

Example 17

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2,3-dimethylbenzylamine was obtained (2,3-dimethylbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a light brown foam. ISP mass spectrum, m/e: 346,4 (M+1 calculated for C23H27F3N3: 346).

Example 18

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-cyanobenzylidene was obtained 4-[(2-methyl-4-pyrrolidin-1-rhinolin-7-ylamino)methyl]benzonitrile in the form of a light brown amorphous solid. ISP mass spectrum, m/e: 343,3 (M+1 calculated for C22H22N4: 343).

Example 19

By Ana is Ogii with example 1, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-tormentilline was obtained (4-terbisil)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a light brown solid. ISP mass spectrum, m/e: 336,2 (M+1 calculated for C21H22F4N3: 335).

Example 20

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2 methoxybenzylamine was obtained (2-methoxybenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a brown solid. ISP mass spectrum, m/e: 348,5 (M+1 calculated for C22H25N3O: 348).

Example 21

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2,2-differentiation was obtained (2,6-diferensial)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a light brown solid. ISP mass spectrum, m/e 354,3 (M+1 calculated for C21H21F2N3: 354).

Example 22

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with benzhydrylamine was obtained benzhydryl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a yellow oil. ISP mass spectrum, m/e: 394,4 (M+1 calculated for C27H27N3: 394).

Example 23

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with furfurylamine was obtained furan-2-ylmethyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine in the de brown oil. ISP mass spectrum, m/e: 308,3 (M+1 calculated for C19H21N3O: 308).

Example 24

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2 thiophenemethylamine was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)thiophene-2-ylmethylamino in the form of a brown oil. ISP mass spectrum, m/e: 324,3 (M+1 calculated for C19H21N3S: 324).

Example 25

(a) By analogy with example 1A), by the reaction of 4-azepin-1-yl-7-iodine-2-methylinosine 4-triphtalocyaninine was obtained (4-azepin-1-yl-2-methylinosine-7-yl)-(4-trifloromethyl)amine as a light brown solid. ISP mass spectrum, m/e: 414,3 (M+1 calculated for C24H26F3N3: 414).

Obtaining input data:

b) In analogy with example 1B), on reaction of 4-chloro-7-iodine-2-methylinosine with hexamethylenimine was obtained 4-azepin-1-yl-7-iodine-2-methylinosine in the form of a nearly white solid, tPL90-93°C.

Example 26

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2 methylbenzylamine was obtained (2-methylbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a yellow solid. ISP mass spectrum, m/e: 332,3 (M+1 calculated for C22H25N3: 332).

Example 27

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 3.5-dimethylbenzylamine was the floor of the EN (3,5-dimethylbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a yellow solid. ISP mass spectrum, m/e: 346,4 (M+1 calculated for C23H27N3: 346).

Example 28

By analogy with example 1, on reaction of 4-azepin-1-yl-7-iodine-2-methylinosine, the product of example 25B), 3-(aminomethyl)pyridine was obtained (4-azepin-1-yl-2-methylinosine-7-yl)pyridine-3-ylmethylamino in the form of a brown viscous oil. ISP mass spectrum, m/e: to 347.5 (M+1 calculated for C22H26N4: 347).

Example 29

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 1-naphthalenemethylamine was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)naphthalen-1-ylmethylamino in the form of a yellow solid. ISP mass spectrum, m/e: 368,3 (M+1 calculated for C25H25N3: 368).

Example 30

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with (R,S)-1-(4-chlorophenyl)ethylamine was obtained (R,S)-[1-(4-chlorophenyl)ethyl]-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a yellow solid. ISP mass spectrum, m/e: 366,2 (M+1 calculated for C22H24ClN3: 366).

Example 31

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-methylbenzylamine was obtained (4-methylbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a light brown solid. ISP mass spectrum, m/e: 332,3 (M+1 calculated for C22H25N3: 332).

Example 32

By analogy with example 1, p is the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 3-methoxybenzylamine was obtained (3-methoxybenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a light brown solid. ISP mass spectrum, m/e: 348,4 (M+1 calculated for C22H25N3About: 348).

Example 33

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2,4-differentiation was obtained (2,4-diferensial)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a brown solid. ISP mass spectrum, m/e: 354,3 (M+1 calculated for C21H21F2N3: 354).

Example 34

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-methoxybenzylamine was obtained (4-methoxybenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a yellow solid. ISP mass spectrum, m/e: 348,4 (M+1 calculated for C22H25N3O: 348).

Example 35

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-(aminomethyl)pyridine was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-4-ylmethylamino in the form of a light brown solid. ISP mass spectrum, m/e: 319,4 (M+1 calculated for C20H22N4: 319).

Example 36

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-(trifluoromethyl)benzylamine was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-(4-trifloromethyl)amine as a yellow solid. ISP mass spectrum, m/e: 386,3 (M+1 calculated for C22H22F3N3: 386).

Example 37

On analogies example 1, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2 chlorobenzylamino was obtained (2-Chlorobenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a light brown solid. ISP mass spectrum, m/e: 352,3 (M+1 calculated for C21H22ClN3: 352).

Example 38

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 3-(aminomethyl)pyridine was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-3-ylmethylamino in the form of a light brown solid. ISP mass spectrum, m/e: 319,4 (M+1 calculated for C20H22N4: 319).

Example 39

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-chlorobenzylamino was obtained (4-chlorbenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a light brown solid. ISP mass spectrum, m/e: 352,3 (M+1 calculated for C21H22ClN3: 352).

Example 40

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 1-aminoindane was obtained indan-1-yl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a brown foam. ISP mass spectrum, m/e: to 344.4 (M+1 calculated for C23H25N3: 344).

Example 41

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin N-methyl-aniline production was obtained methyl(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)phenylamine as a light-brown, the second foam. ISP mass spectrum, m/e: 318,3 (M+1 calculated for C21H23N3: 318).

Example 42

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-(ethylaminomethyl)pyridine was obtained ethyl-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-4-ylmethylamino in the form of a brown viscous oil. ISP mass spectrum, m/e: 347,4 (M+1 calculated for C22H26N4: 347).

Example 43

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 3-(methylaminomethyl)pyridine was obtained methyl(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)pyridine-3-ylmethylamino in the form of a light brown viscous oil. ISP mass spectrum, m/e: to 333.3 (M+1 calculated for C21H24N4: 333).

Example 44

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 1,2,3,4-tetrahydroisoquinoline was obtained 7-(3,4-dihydro-1H-isoquinoline-2-yl)-2-methyl-4-pyrrolidin-1-rhinolin in the form of a light brown viscous oil. ISP mass spectrum, m/e: to 344.4 (M+1 calculated for C23H25N3: 344).

Example 45

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2-(2-chlorophenyl)ethylamine was obtained [2-(2-chlorophenyl)ethyl]-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a light brown foam. ISP mass spectrum, m/e: 366,2 (M+1 calculated for C22H24ClN3: 366).

Example 46

By analogy the AI with example 1, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 3-methylthiophene-2-methylamine was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-(3-methylthiophene-2-ylmethyl)amine as a yellow foam. ISP mass spectrum, m/e: 338,3 (M+1 calculated for C20H23N3S: 338).

Example 47

Suspension 0,338 mg (1 mmol) of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin, 0,81 g (8 mmol) of trimethylacetamido, 0,414 g (3 mmol) of potassium carbonate (dry) and 20 mg (0.1 mmol) of copper iodide (I) in DMF (10 ml) was heated at 150°C (oil bath temperature) in an argon atmosphere for 20 hours the Reaction mixture was separated between EtOAc and water, the layers were separated, the organic layer was washed twice with water, dried over sulfate sodium and evaporated in vacuum. The residue was applied onto a column of silica gel with CH2Cl2/MeOH/NH4OH (20:1:0,2) as eluent. The Association of the purified fractions and evaporation in vacuum resulted in the receipt of 175 mg (50.4 percent) of the desired 2,2-dimethyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide in the form of a light brown solid. ISP mass spectrum, m/e: 312,3 (M+1 calculated for C19H25N3O: 312).

Example 48

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with cyclobutanecarboxylic was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide cyclobutanecarbonyl acid as a pale yellow solid. ISP mass spectrum m/e: 310,3 (M+1, calculated for C19H23N3A: 310).

Example 49

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with cyclopropanecarboxamide was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide cyclopropanecarbonyl acid as a pale yellow solid. ISP mass spectrum, m/e: usd296.4 (M+1 calculated for C18H21N3O: 296).

Example 50

By analogy with example 47, the reaction of (R)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (product of example 10B) with propionamide was obtained (R)-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]propionamide in the form of a brown solid. ISP mass spectrum, m/e: 328,4 (M+1 calculated for C19H25N3O2: 328).

Example 51

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with propionamide was obtained N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide in the form of a brown viscous oil. ISP mass spectrum, m/e: 284,2 (M+1 calculated for C17H21N3O: 284).

Example 52

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with isovaleramide was obtained 3-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)butyramide in the form of a crystalline white-yellow solid. ISP mass spectrum, m/e: 312,3 (M+1 calculated for C19H25N3O: 312).

Example 53

a) P is similar to example 47, the reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol with trimethylacetamido was obtained (S)-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]-2,2-dimethylpropanamide in the form of an amorphous white-yellow solid. ISP mass spectrum, m/e: 342,3 (M+1 calculated for C20H27N3O2: 342).

Obtaining source material

b) a Solution of 3.5 g (11.5 mmol) of 4-chloro-7-iodine-2-methylinosine and of 2.92 g (28.8 mmol) of (S)-2-(hydroxymethyl)pyrrolidine 1-methyl-2-pyrrolidone (50 ml) was heated at 100°C (oil bath temperature) for 24 h in an argon atmosphere. For completion of the reaction was added 2.2 ml (S)-2-(hydroxymethyl)pyrrolidine and the solution was heated at 100°C for 24 h under argon. The solution is then evaporated in vacuum (4 mbar) at 100°C. the Residue was applied onto a column of silica gel with CH2Cl2/MeOH/NH4OH (95:5:0,2) as eluent. The Association of the purified fractions and evaporation in vacuum resulted in obtaining 2.7 g (64%) of the desired (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol as a light brown solid. ISP mass spectrum, m/e: 369,1 (M+1 calculated for C15H17IN2O: 369).

Example 54

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2 Pyramida was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide, furan-2-carboxylic acid as light-W is LEGO solids. ISP mass spectrum, m/e: was 322.3 (M+1 calculated for C19H19H3About2: 322).

Example 55

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with PP was obtained N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amid in the form of a light yellow solid. ISP mass spectrum, m/e: to 333.3 (M+1 calculated for C20H20N4About: 333).

Example 56

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-cyanobenzylidene was obtained 4-cyano-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide in the form of a light brown solid. ISP mass spectrum, m/e: 357,3 (M+1 calculated for C22H20N4O: 357).

Example 57

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 2 fermentation was obtained 2-fluoro-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide as a pale yellow solid. ISP mass spectrum, m/e: 350,3 (M+1 calculated for C21H20FN3O: 350).

Example 58

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 4-methoxybenzamide was obtained 4-methoxy-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide in the form of a light brown solid. ISP mass spectrum, m/e: 362,4 (M+1 calculated for C22H23N3O2: 362).

Example 59

By analogy with example 47, the reaction IOD-2-methyl-4-pyrrolidin-1-rhinolin 4-fermentation was obtained 4-fluoro-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide in the form of a light brown solid. ISP mass spectrum, m/e: 350,3 (M+1 calculated for C21H20FN3O: 350).

Example 60

By analogy with example 47, by the reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with isonicotinamide was obtained N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)isonicotinamide in the form of a light brown solid. ISP mass spectrum, m/e: to 333.3 (M+1 calculated for C20H20N4O: 333).

Example 61

By analogy with example 47, the reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl] methanol (product of example 53b) with PP was obtained (S)-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]nicotinamide as an almost white solid. ISP mass spectrum, m/e: 363,3 (M+1 calculated for C21H22N4O2: 363).

Example 62

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin N-nicotine amide, xanthosoma as phosphine (instead of rac BINAP), cesium carbonate as the base (instead of tert-butyl sodium) in 1,4-dioxane as solvent (General procedure: Buchwald, etc: Org. Lett., 2000, 2, 1104) was obtained N-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-nicotinamide as a yellow solid. ISP mass spectrum, m/e: 347,4 (M+1 calculated for C21H22N4O: 347).

Example 63

By analogy with example 47, the reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol (product when the EPA 53b) with furisemide was obtained [4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-furan-2-carboxylic acid as a pale yellow substance. ISP mass spectrum, m/e: 352,4 (M+1 calculated for C20H21N3About3: 352).

Example 64

b) In a dried reaction flask, treated with argon, a suspension of 169 mg (0.5 mmol) of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin and 57 mg (0.6 mmol) of methanesulfonamide, 325 mg (1 mmol) of cesium carbonate, with 1.9 mg (0.01 mmol) of copper iodide (I) in 1,4-dioxane was treated at room temperature of 5.7 mg (0.05 mmol) of TRANS-diaminocyclohexane and the mixture was heated at 110°C (oil bath temperature) for 48 h in the atmosphere argon (General method: Buchwald J. am. Chem. Soc., p7727, 2001). The reaction mixture was then cooled to room temperature, was dissolved in methylene chloride and filtered. The filtrate was concentrated in vacuo, the residue was applied onto a column of silica gel with CH2Cl2/MeOH/NH4OH (9:1:0,5) as eluent. The Association of the purified fractions and evaporation in vacuum resulted in the receipt of 29 mg (25,5%) of the desired N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)methanesulfonamide, which was recrystallized from methylene chloride: light brown solid. ISP mass spectrum, m/e: 306,3 (M+1 calculated for C15H19IN3O2S: 306).

Example 65

In analogy to example 64, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with (4-were)a sulfonamide was obtained 4-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzosulfimide in the form of p is almost white solid. ISP mass spectrum, m/e: 382,4 (M+1 calculated for C21H23N3O3S: 382).

Example 66

In analogy to example 64, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with pyridyl-3-sulfonamide was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide pyridine-3-sulfonic acid in the form of an almost white solid. ISN mass spectrum, m/e: 367,1 (M-1 calculated for C19H20N4O2S: 367).

Example 67

In analogy to example 64, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin 2-chlorothiophene-2-sulfonamide was obtained (2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide 5-chlorothiophene-2-sulphonic acid in the form of an almost white solid. ISN mass spectrum, m/e: 406,3 (M-1 calculated for C18H18ClN3O2S2: 406).

Example 68

In analogy to example 64, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin N-methylbenzenesulfonamide was obtained M-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-benzosulfimide as an almost white solid. ISP mass spectrum, m/e: 382,4 (M+1 calculated for C21H23N3O2S: 382).

Example 69

A solution of 0.1 g (0.27 mmol 2-methyl-4,6-dipyrrole-1-rhinolin-7-ylamine hydrochloride (x1,58 HCl), the product of example 70 in acetic acid (0,22 ml) was treated with 0.1 ml (1,08 mmol) of acetic anhydride and then stirred at room temperature for 19 hours actionnow the mixture was concentrated in vacuum, brought the pH to 9 with concentrated ammonia and then twice was extracted with CH2CL2. The organic phase is washed with water, saturated salt solution and dried over magnesium sulfate. The solvent was removed in vacuo, the residue triturated with ether (10 ml) and was treated dropwise 0.3 ml of 3 N HCL in Meon. The obtained brown crystalline solid was filtered by suction and dried in vacuum, obtaining of 58.7 mg (89%) of N-(2-methyl-4,6-dipyrrole-1-rhinolin-7-yl)ndimethylacetamide hydrochloride as a brown solid. ISP mass spectrum, m/e: 339,3 (M+1 calculated for C20H27N4O: 339).

Example 70

a) a Suspension of 0.28 g (0.86 mmol) of 2-methyl-7-nitro-4,6-dipyrrole-1-rhinolin in the Meon (10 ml) was treated with 60 mg of Pd/C (10%) and then was first made in an atmosphere of H2for 2 h at room temperature to complete the reaction. The catalyst was filtered, the filtrate was concentrated in vacuum. The residue is triturated with ether (15 ml) and was treated dropwise 1 ml of 3 N HCL in Meon to obtain 209 mg (97,4%) of 2-methyl-4,6-dipyrrole-1-rhinolin-7-ylamine hydrochloride (x1,58 HCl) as a light brown solid. ISP mass spectrum, m/e: 297,4 (M+1 calculated for C18H24H4: 297).

Obtaining input data:

b) 20 g (156 mmol) 4-fluoro-3-nitroaniline, to 18.9 ml (134 mmol) of ethylacetoacetate in cyclohexane (35 ml) on amityvale monohydrate p-toluensulfonate acid (0.24 g) and was heated for 9 h at boiling under reflux. The solvent was removed in vacuo, the residue was applied onto a column of silica gel with AcOEt/n-hexane (1:1)as eluent. The Association of the purified fractions and evaporation in vacuum resulted in obtaining 4.3 g (12.5%) of the ethyl ester of 3-(4-fluoro-3-nitrophenylamino)but-2-ene acid as yellow crystals. ISN mass spectrum, m/e: 267,2 (M-1 calculated for C12H13FN2O4: 267).

C) a Solution of 3.6 g (13,42 mmol) of ethyl ester of 3-(4-fluoro-3-nitrophenylamino)-but-2-ene acid in dotime (10 ml) was added dropwise to 56 ml Dowtherm heated to 250°C. Heating was continued for 15 minutes, then the suspension was cooled to room temperature, was added heptane, the precipitate was collected by filtration, washed with heptane and ether and then dried under vacuum to obtain 1.9 grams ring product light brown solid substance in the form of a mixture of two regioisomers of isomers containing 1.26 g of the desired 6-fluoro-2-methyl-7-nitroquinoline-4-ol. EI mass spectrum, m/e: to 222.2 (M, calculated for C10H7N2O3: 222). The product was used in the next stage without additional purification.

g) the above material (2,05 g) was heated in 9.1 ml of POCl3within 1.5 hours After removal of the solvent the residue was applied onto a column of silica gel with AcOEt/n-hexane (3:7)as eluent. The Association of the purified fractions and evaporation in vacuo gave the to obtain 0.31 g (13,8%) 4-chloro-6-fluoro-2-methyl-7-nitroquinoline in the form of a brown solid. EI mass spectrum, m/e: 240,1 (M, calculated for C10H6FN2O2: 240).

d) a Solution of 0.29 g (1,21 mmol) 4-chloro-6-fluoro-2-methyl-7-nitroquinoline in pyrrolidine (2 ml, 24 mmol) was heated at 80°C (bath temperature) for 18 hours the Excess pyrrolidine was removed in vacuo, the residue was transferred into methylene chloride, which was washed with water, with brine and then dried over magnesium sulfate. The solvent was removed in vacuum to obtain 0.34 g (79%) of the desired 2-methyl-7-nitro-4,6-dipyrrole-1-rhinolin as a dark red solid. ISP mass spectrum, m/e: 327,3 (M+1 calculated for C18H22N4O2: 327).

Example 71

By analogy with example 1, on reaction of 7-iodine-2-methyl-4-pyrrolidin-1-rhinolin with 3-amino-2-chloropyridine was obtained (2-chloropyridin-3-yl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine as a brown foam. ISP mass spectrum, m/e: 339,3 (M+1 calculated for C22H24ClN3: 339).

Example 72

By analogy with example 1, on reaction of (R)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example 10B) with a 4-aminobenzonitrile was obtained (R)-4-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile in the form of a light brown solid. ISP mass spectrum, m/e: 373,4 (M+1 calculated for C23H24N4O: 373).

Example 73

In analogy to example 64, on reaction of (R)-7-yo is-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example 10B) with a 4-cyanobenzylidene was obtained (R)-4-cyano-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]benzamide in the form of a light brown solid. ISP mass spectrum, m/e: is 401.5 (M+1 calculated for C24H24N4O2: 401).

Example 74

In analogy to example 64, on reaction of (R)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example 10B) with ndimethylacetamide was obtained (R)-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]ndimethylacetamide in the form of a light brown solid. ISP mass spectrum, m/e: 314.4 M. (M+1 calculated for C18H23N3O2: 314).

Example 75

In analogy to example 64, on reaction of (R)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example 10B) with a 4-fermentation and conversion of the free base cleaners containing hydrochloride salt was obtained (R)-4-fluoro-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]benzamide hydrochloride as an almost white solid. ISP mass spectrum, m/e: 394,4 (M+1 calculated for C23H24FN3About2: 394).

Example 76

By analogy with example 1, on reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol (product of example 53b) with 4-aminobenzonitrile was obtained (S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile in the form of a yellow solid. ISP mass spectrum, m/e: 359,3 (M+1 calculated for C22H22N4About: 359).

Example 77

By analogy with example 1, on reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol (product when the EPA 53b) with 3-aminopyridine was obtained (S)-{1-[2-methyl-7-(pyridine-3-ylamino)quinoline-4-yl]pyrrolidin-2-yl}methanol light brown solid. ISP mass spectrum, m/e: 335,3 (M+1 calculated for C20H22N4O: 335).

Example 78

By analogy with example 47, the reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl] methanol (product of example 53b) 2-furamide was obtained [4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-furan-2-carboxylic acid as a pale yellow solid. ISP mass spectrum, m/e: 352,4 (M+1 calculated for C20H21N3About3: 352).

Example 79

By analogy with example 1, on reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol (product of example 53b) with 3-amino-2-chloropyridine was obtained (S)-{1-[7-(2-chloropyridin-3-ylamino)-2-methylinosine-4-yl]pyrrolidin-2-yl}methanol as an amorphous brown solid. ISP mass spectrum, m/e: 369,3 (M+1 calculated for C20H21ClN4O: 369).

Example 80

In analogy to example 64, on reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol (product of example 53b) with cyclopropanecarboxamide was obtained [4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]amide (3)-cyclopropanecarbonyl acid as an amorphous light brown solid. ISP mass spectrum, m/e: 326,3 (M+1 calculated for C19H23N3O2: 326).

Example 81

In analogy to example 64, on reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol (product of example 53b)- cyanobenzene was obtained (S)-4-cyano-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide as a pale yellow solid. ISP mass spectrum, m/e: 387,3 (M+1 calculated for C23H22N4About3: 387).

Example 82

In analogy to example 64, on reaction of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol (product of example 53b) with 4-fermentation was obtained (S)-4-fluoro-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide in the form of a light brown solid. ISP mass spectrum, m/e: 380,4 (M+1 calculated for C22H22FN3O2: 380).

Example 83

a) In analogy with example 1, on reaction of (S)-7-iodine-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine hydrochloride with 3-aminopyridine was obtained (S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]pyridine-3-ylamine as a brown foam. ISP mass spectrum, m/e: 335,4 (M+1 calculated for C29H22N4O: 335).

Obtaining source material

b) In analogy with example 1B), on reaction of 4-chloro-7-iodine-2-methylinosine with (S)-3-ethoxypyrrolidine (2 molar equivalents) in 1-methyl-2-pyrrolidone as solvent at 140°and converting the free base cleaners containing hydrochloride salt was obtained (S)-7-iodine-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine hydrochloride in the form of an almost white solid. ISP mass spectrum, m/e: 369,2 (M+1 calculated for C15H17IN2About: 369).

Example 84

In analogy to example 64, on reaction of (S)-7-iodine-4-(3-ethoxypyrrolidine-1-yl)-2-METHYLPHENOL is on hydrochloride (the product of example b) with PP was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]nicotinamide as a light brown solid. ISP mass spectrum, m/e: 365,2 (M+1 calculated for C21H22N4O2: 365).

Example 85

In analogy to example 64, on reaction of (S)-7-iodine-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine hydrochloride (the product of example b) propionamide was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]propionamide as a pale yellow solid. ISP mass spectrum, m/e: 314.4 M. (M+1 calculated for C18H23N3O2: 314).

Example 86

In analogy to example 64, on reaction of (S)-7-iodine-4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine hydrochloride (the product of example b) with 4-cyanobenzoic was obtained (S)-4-cyano-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide in the form of a brown solid. ISP mass spectrum, m/e: 387,3 (M+1 calculated for C23H22N4O2: 387).

Example 87

a) In analogy to example 64, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride with cyclopropanecarboxamide was obtained [4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-cyclopropanecarboxylic acid as a light brown solid. ISP mass spectrum, m/e: 340,4 (M+1 calculated for C20H25N3O2: 340).

Obtaining source material

b) In analogy with example 1B), on reaction of 4-chloro-7-iodine-2-methylinosine with (S)-3-ethoxypyrrolidine (2 molar equivalents) in 1-methyl-pyrrolidone as solvent at 140° With the conversion of the free base cleaners containing hydrochloride salt was obtained (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride as a light brown solid. ISP mass spectrum, m/e: 383,2 (M+1 calculated for C16H19IN2O: 383).

Example 88

In analogy to example 64, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) 2-pyrilamine was obtained [4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-furan-2-carboxylic acid as a white solid. ISP mass spectrum, m/e: 366,3 (M+1 calculated for C21H23N3O2: 366).

Example 89

By analogy with example 1, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with 4-aminobenzonitrile was obtained (S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile as a pale yellow solid. ISP mass spectrum, m/e: 373,5 (M+1 calculated for C23H24N4About: 373).

Example 90

In analogy to example 64, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with PP was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]nicotinamide as a light brown solid. ISP mass spectrum, m/e: 377,4 (M+1 calculated for C22H24N4O2: 377)

Example 91

By analogy with example 1, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with 4-aminopyridine was obtained (S)-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]pyridine-3-yl-amine as a light brown solid. ISP mass spectrum, m/e: 349,5 (M+1 calculated for C21H24N4O: 349).

Example 92

In analogy to example 64, on reaction of (S)-4-(3-ethoxy-pyrrolidin-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) propionamide was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]propionamide in the form of a light brown solid. ISP mass spectrum, m/e: 328,4 (M+1 calculated for C19H25N3O2: 328).

Example 93

In analogy to example 64, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) 2-fermentation was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-4-perbenzoic in the form of a light brown solid. ISP mass spectrum, m/e: 394,4 (M+1 calculated for C23H24FN3O2: 394).

Example 94

In analogy to example 64, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with 4-cyanobenzene and conversion of the free base cleaners containing hydrochloride salt was obtained (S)-4-cyano-N-[4-(3-ethoxyphenol the DIN-1-yl)-2-methylinosine-7-yl]benzamide hydrochloride as a light brown solid. ISP mass spectrum, m/e: is 401.5 (M+1 calculated for C24H24N4O2: 401).

Example 95

In analogy to example 64, on reaction of (S)-4-(3-ethoxy-pyrrolidin-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with 4-trimethylacetamido and conversion of the free base cleaners containing hydrochloride salt was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-2,2-dimethylpropanamide hydrochloride as a light brown solid. ISP mass spectrum, m/e: 356,4 (M+1 calculated for C21H29N3O2: 356).

Example 96

In analogy to example 64, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with (4-chlorophenyl)ndimethylacetamide was obtained (S)-2-(4-chlorophenyl)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]ndimethylacetamide in the form of a light brown solid. ISP mass spectrum, m/e: 424,5 (M+1 calculated for C24H26N3O2Cl: 424).

Example 97

In analogy to example 64, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) (3-pyridyl)ndimethylacetamide was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-2-pyridine-2-ylacetamide in the form of a light brown solid. ISP mass spectrum, m/e: 391,2 (M+1 calculated for C23H26N4O2: 391).

Example 98

In analogy to example 64, on R. the action (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with (4-methoxyphenyl)ndimethylacetamide was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-2-(4-methoxyphenyl)ndimethylacetamide in the form of a light brown the solids. ISP mass spectrum, m/e: 420,4 (M+1 calculated for C25H29N3About3: 420).

Example 99

In analogy to example 64, on reaction of (S)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with (3-triptoreline)ndimethylacetamide was obtained (S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-2-(3-triptoreline)ndimethylacetamide in the form of a light brown solid. ISP mass spectrum, m/e: 458,5 (M+1 calculated for C25H26F3N3O2: 458).

Example 100

a) In analogy with example 1, on reaction of (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine 4-aminobenzonitrile was obtained (S)-4-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile in the form of a brown solid. ISP mass spectrum, m/e: 373,4 (M+1 calculated for C23H24N4O: 373).

Obtaining source material

b) In analogy with example 1B), on reaction of 4-chloro-7-iodine-2-methylinosine with (S)-2-(methoxymethyl)pyrrolidine was obtained (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine in the form of a beige solid. ISP mass spectrum, m/e: 383,1 (M+1 calculated for C16H19IN2O: 383).

Example 101

By analogy with example 1, on reaction of (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example b) with 4-fornerino was obtained (S)-(4-forfinal)[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amine as brown amorphous solid. ISP mass spectrum, m/e: 366,3 (M+1 calculated for C22H24FN3O: 366).

Example 102

By analogy with example 1, on reaction of (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example b) with 3-aminopyridine was obtained (S)-4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]pyridine-3-ylamine as a pale yellow solid. ISP mass spectrum, m/e: 349,5 (M+1 calculated for C21H24N4O: 349).

Example 103

In analogy to example 64, on reaction of (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example b) cyclopropanecarboxamide was obtained [4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amide (S)-cyclopropanecarboxylic acid as an amorphous brown solid. ISP mass spectrum, m/e: 340,3 (M+1 calculated for C20H25N3O2: 340).

Example 104

In analogy to example 64, on reaction of (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example b) trimethylacetamido was obtained (S)-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]-2,2-dimethylpropanamide in the form of a light brown solid. ISP mass spectrum, m/e: 356,3 (M+1 calculated for C21H29N3O2: 356).

Example 105

By analogy with example 1, on reaction of (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example b) cyclop what pilltramadol was obtained (S)-cyclopropylmethyl-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amine as a yellow foam. ISP mass spectrum, m/e: 326,5 (M+1 calculated for C20H27N3O: 326).

Example 106

In analogy to example 64, on reaction of (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example b) propionamide was obtained (S)-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]propionamide as an almost white solid. ISP mass spectrum, m/e: 328,4 (M+1 calculated for C19H25N3O2: 328).

Example 107

In analogy to example 64, on reaction of (S)-7-iodine-4-(2-methoxypiperidine-1-yl)-2-methylinosine (the product of example b) with 4-cyanobenzoic was obtained (S)-4-cyano-N-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]benzamide in the form of a light brown amorphous solid. ISP mass spectrum, m/e: is 401.5 (M+1 calculated for C24H24N4O2: 401).

Example 108

a) In analogy with example 1, on reaction of (S)-4-(2-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride with 4-fornerino and conversion of the free base to the hydrochloride was obtained (S)-[4-(2-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]-(4-forfinal)amine hydrochloride in the form of an almost white solid. ISP mass spectrum, m/e: 380,3 (M+1 calculated for C23H26FN3O: 380).

Obtaining input data:

b) a Solution of 1.29 g (3.5 mmol) of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl] methanol (about the TPC of example 53b) in THF (40 ml) was treated at room temperature 0,89 g (7,88 mmol) of potassium tert-butylate, was stirred for 30 minutes and was added dropwise 0,636 ml (7,88 mmol) ethyliodide. After 2.5 h was added 0.25 ml of ethyliodide and the reaction mixture was stirred at room temperature for 12 hours the Mixture was separated between EtOAc and water, the layers were separated, the organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was purified accelerated by chromatography on a column of silica gel with 3-5% Meon in CH2Cl2as eluent. The Association of purified fractions, concentration in vacuo and conversion of the free base in cleaners containing hydrochloride salt (processing of 1.25 M HCl in the Meon) resulted in the receipt of 910 mg (60%) of the desired (S)-4-(2-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride as a pale yellow solid. ISP mass spectrum, m/e: 397,3 (M+1 calculated for C17H21IN2O: 397).

Example 109

By analogy with example 1, on reaction of (S)-4-(2-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with 3-aminopyridine and receiving cleaners containing hydrochloride salt was obtained (S)-[4-(2-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]pyridine-3-ylamine hydrochloride as a pale brown amorphous foam. ISP mass spectrum, m/e: 363,1 (M+1 calculated for C22H26N4O: 363).

Example 110

In analogy to example 64, on reaction of (S)-4-(2-ethoxypyrrolidine-1-yl)-7-iodine-2-METHYLPHENOL is on hydrochloride (the product of example b) 2-furisemide and receiving cleaners containing hydrochloride salt was obtained hydrochloride [4-(2-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-furan-2-carboxylic acid in the form of almost white solid substances. ISP mass spectrum, m/e: 380,3 (M+1 calculated for C22H25N3O3: 380).

Example 111

By analogy with example 1, on reaction of (R/S)-7-chloro-4-(2-1-pyrrolidinyl)quinoline (Synthesis: 1995, R) with 4-aminobenzonitrile with a complex of palladium SK-CC01-A (Solvias AG, Basel) instead of the system Pd(OAc)2/BINAP was obtained (R/S)-4-[4-(2-methylpyrrolidine-1-yl)quinoline-7-ylamino]benzonitrile in the form of a light brown solid. ISP mass spectrum, m/e: 329,3 (M+1 calculated for C21H20N4: 329).

Example 112

a) In analogy with example 1, on reaction of (S)-4-(2-cyclopropanecarbonitrile-1-yl)-7-iodine-2-methylinosine hydrochloride with 4-aminobenzonitrile and conversion of the free base to the hydrochloride was obtained (S)-4-[4-(2-cyclopropanecarbonitrile-1-yl)-2-methylinosine-7-ylamino]benzonitrile hydrochloride in the form of an almost white solid. ISP mass spectrum, m/e: 413,5 (M+1 calculated for C26H28N4O: 413).

Obtaining input data:

b) In analogy with example b), the alkylation of (S)-[1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-2-yl]methanol (product of example 53b) (methyl bromide)picloram and converting the free base to the hydrochloride was obtained (S)-4-(2-cyclopropanecarbonitrile-1-yl)-7-iodine-2-methylinosine hydrochloride as a pale yellow solid. ISP mass spectrum, m/e: 23,3 (M+1, calculated for C19H23IN2O: 423).

Example 113

a) In analogy with example 1, on reaction of (S) - 4-(2-cyclopropanecarbonitrile-1-yl)-7-iodine-2-methylinosine hydrochloride (the product of example b) with 3-aminopyridine and conversion of the free base to the hydrochloride was obtained (S)-[4-(2-cyclopropanecarbonitrile-1-yl)-2-methylinosine-7-yl]pyridine-3-ylamine hydrochloride as a brown foam. ISP mass spectrum, m/e: 389,2 (M+1 calculated for C24H28N4O: 389).

Example 114

a) In analogy to example 64, on reaction of (R)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride with 4-cyanobenzoic was obtained (R)-4-cyano-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]benzamide in the form of a yellow solid. ISP mass spectrum, m/e: 401,4 (M+1 calculated for C24H24N4O2: 401).

Obtaining source material

b) In analogy with example 1B), on reaction of 4-chloro-7-iodine-2-methylinosine with (R)-3-hydroxypyrrolidine (a 2.5 molar equivalents) in 1-methyl-2-pyrrolidone as solvent at 140°was obtained (R)-1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-3-ol in the form of an almost white solid. ISP mass spectrum, m/e: 355,2 (M+1 calculated for C14H15IN2About: 355).

C) In analogy with example b), the alkylation of (R)-1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-3-ol with ethyliodide and pre the education of the free base to the hydrochloride was obtained (R)-4-(3-ethoxypyrrolidine-1-yl)-7-iodine-2-methylinosine hydrochloride as a light brown solid. ISP mass spectrum, m/e: 383,2 (M+1 calculated for C16H19IN2O: 383).

Example 115

a) In analogy to example 64, on reaction of (S)-4-(3-cyclopropylmethoxy-1-yl)-7-iodine-2-methylinosine with PP was obtained (S)-N-[4-(3-cyclopropylmethoxy-1-yl)-2-methylinosine-7-yl]nicotinamide as a light yellow solid. ISP mass spectrum, m/e: 403,5 (M+1 calculated for C24H26N4O2: 403).

Obtaining input data:

b) In analogy with example 1B), on reaction of 4-chloro-7-iodine-2-methylinosine with (S)-3-hydroxypyrrolidine (a 2.5 molar equivalents) in 1-methyl-2-pyrrolidone as solvent at 140°was obtained (S)-1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-3-ol as a light brown solid. ISP mass spectrum, m/e: 355,2 (M+1 calculated for C14H15IN2O: 355).

C) In analogy with example b), the alkylation of (S)-1-(7-iodine-2-methylinosine-4-yl)pyrrolidin-3-ol with (methyl bromide)cyclopropane was obtained (S)-4-(3-cyclopropylmethoxy-1-yl)-7-iodine-2-methylinosine in the form of an orange oil. ISP mass spectrum, m/e: 409,2 (M+1 calculated for C18H21IN2O: 409).

Example 116

a) In analogy to example 64, on reaction of 7-iodine-2,6-dimethyl-4-pyrrolidin-1-rhinolin furan-2-carboxamide was obtained (2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)amide, furan-2-carboxylic acid in the form of blaspemy. ISP-MS: m/e=336,3 ([M+H]+).

The intermediate connection:

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

A suspension of 3-iodine-4-methylaniline (50.0 g, 215 mmol), ethylacetoacetate (30,7 g, 236 mmol) and monohydrate toluene-4-sulfonic acid (430 mg, of 2.15 mmol) was boiled under reflux for 2 h in cyclohexane (100 ml), allowing produced water to be collected in the trap Dean-stark, then after cooling, the undissolved material was removed by filtration and the filtrate was evaporated. The residue was dissolved in Dowtherm® (25 ml) and added dropwise to a hot (approximately 250° (C) Dowtherm® A. After 15 minutes the reaction mixture was cooled to room temperature, then was added heptane (150 ml) and the precipitate collected by filtration. This material is triturated in ethyl acetate to obtain 1:1 mixture of 7-iodine-2,6-methyl-1H-quinoline-4-it 5-iodine-2,6-dimethyl-1H-quinoline-4-it (46,4A), which were treated with chloride oxides of phosphorus (130 ml) and N, N-dimethylformamide (0.6 ml). The resulting solution was stirred at 50°C for 20 minutes, then carefully poured into ice and brought the pH to 7 with 25% aqueous ammonium hydroxide solution. After extraction with ethyl acetate the organic layer was washed with brine, dried (MgSO4) and was evaporated. Recrystallization of the mixture thus obtained product (4-chloro-7-iodine-2,6-dimethylphenol and 4-chloro-5-iodine-2,6-dimethylphenol) in hexane/ethyl is cetate 9:1 (150 ml) resulted in obtaining specified in the connection header (of 7.55 g, 11%). Light brown solid, ISP-MS: m/e=318,1 ([M+H]+).

C) 7-Iodine-2,6-dimethyl-4-pyrrolidin-1-rhinolin

A solution of 4-chloro-7-iodine-2,6-dimethylaniline (200 mg, to 0.63 mmol) was boiled under reflux in pyrrolidine (1.5 ml) for 3 hours After evaporation of excess pyrrolidine the residue was transferred into ethyl acetate and washed with 2 M aqueous solution of sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and was evaporated. Chromatography (SiO2CH2Cl2/MeOH/NH4OH 95:5:0.25 in) resulted in obtaining specified in the title compound (193 mg, 87%). Light brown solid, ISP-MS: m/e=353,2 ([M+H+]).

Example 117

In analogy to example 64, on reaction of 7-iodine-2,6-dimethyl-4-pyrrolidin-1-rhinolin with propionamide was obtained N-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide in the form of a light yellow foam. ISP-MS: m/e=298,4 ([M+H]+).

Example

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

Pills
The active ingredient200 mg
Microcrystalline cellulose155 mg
Corn starch25 mg
25 mg
The hypromellose20 mg
425 mg

Example B

The compound of the formula I can be used in a known manner as an active ingredient to obtain 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 obtained in the usual way:

IngredientsPills
The compound of the formula Iof 10.0-100.0 mg
Lactose125,0 mg
Maize starch75,0 mg
Talc4.0 mg
Magnesium stearate1.0 mg

EXAMPLE D

Capsules containing the following ingredients can be obtained in the usual way:

IngredientsOn capsule
The compound of the formula I25.0 mg
Lactose150,0 mg
Maize starch20.0 mg
Talc5.0 mg

EXAMPLE D

Injectable solutions may have the following composition:

The compound of the formula I3.0 mg
Gelatin150,0 mg
Phenol4,7 mg
Water for injection solutionsTo 1.0 ml

1. Derivatives of quinoline of formula (I)

in which R1and R2independently selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkylcarboxylic, cycloalkylcarbonyl, phenyl, benzyl, unsubstituted and substituted by halogen, cyano, trifluoromethyl, alkyl, alkoxygroup, benzylcarbamoyl, pyridinyl, furil, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-thiophenyl-SO2or R1and R2together with the N atom to which they are attached, form piperidino, pyrrolidinyl, morpholinyl, azepane, 3,4-dihydro-1H-ethenolysis, and where the heterocyclic ring optionally substituted by one or more substituents, an is isimo selected from alkyl and alkoxy;

R3represents hydrogen, alkyl;

R4represents hydrogen;

And together with the nitrogen atom, which is attached to the quinoline ring is pyrrolidinyl, azepane and ring And optionally substituted with one to three substituents independently selected from alkoxy, hydroxyalkyl, alkoxyalkyl;

and their pharmaceutically acceptable salts and esters.

2. Compounds according to claim 1, where R1and R2independently selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkylcarboxylic, cycloalkylcarbonyl, phenyl, benzyl, unsubstituted and substituted by halogen, cyano, trifluoromethyl, alkyl, alkoxygroup, benzylcarbamoyl, pyridinyl, furil, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-thiophenyl-SO2or R1and R2together with the N atom to which they are attached, form piperidino, pyrrolidinyl, morpholinyl, azepane, 3,4-dihydro-1H-ethenolysis, and where the heterocyclic ring optionally substituted by one or more substituents, independently selected from alkyl and alkoxy; and

And together with the nitrogen atom, which is attached to the quinoline ring is pyrrolidinyl, azepane and ring And optionally substituted with one to three substituents independently selected from alkoxy, hydroxyalkyl, alkoxyalkyl is.

3. Compounds according to claim 1, in which R3represents hydrogen or alkyl.

4. Compounds according to claim 3, where R3represents methyl.

5. Compounds according to claim 1, in which a represents pyrrolidin or ASEAN, optionally substituted alkoxyalkyl, hydroxyalkyl or alkoxy.

6. Compounds according to claim 5, in which a represents pyrrolidine, optionally substituted by hydroxymethyl or methoxymethyl.

7. Compounds according to claim 1, in which one of R1and R2represent hydrogen or alkyl, and the other is independently selected from alkyl, cycloalkyl, cycloalkenyl, alkylcarboxylic, cycloalkylcarbonyl, phenyl, thiophenyl, pyridinyl, furil, indanyl, phenyl-SO2-thiophenyl-SO2-, pyridinyl-SO2and where the phenyl group is optionally substituted with one to three substituents, independently selected from alkyl, cyano, halogen, alkoxy and trifloromethyl, or R1and R2together with the N atom to which they are attached, form asianave, 3,4-dihydro-1H-isoquinoline, piperidine, pyrolidine or morpholine ring, which is optionally substituted with one to three substituents, independently selected from alkyl and alkoxy.

8. Compounds according to claim 1, in which one of R1and R2represents hydrogen or methyl and the other is independently selected from alkylcarboxylic, cyclo is kilcarbery, alkoxybenzyl, pyridyl-SO2pyridinyl and cycloalkylcarbonyl.

9. Compounds according to claim 1, in which one of R1and R2represents hydrogen.

10. Compounds according to claim 1, selected from

(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)aminocyclopropane acids;

2,2-dimethyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide;

4-(2-methyl-4-pyrrolidin-1-rhinolin-7-ylamino)benzonitrile;

3-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)butyramide;

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

N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)nicotinamide;

(2.2-dimethylpropyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

4-cyano-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide;

(2-methoxybenzyl)-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amine;

(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-thiophene-2-ylmethylamino;

4-fluoro-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)benzamide;

N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)isonicotinamide;

(S)-N-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]nicotinamide;

N-methyl-N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)nicotinamide;

[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-furan-2-carboxylic acid;

N-(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)-methanesulfonamide is;

(2-methyl-4-pyrrolidin-1-rhinolin-7-yl)amide pyridine-3-sulfonic acid;

(R)-4-[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

(S)-4-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

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

[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]amide (S)-cyclopropanecarbonyl acids;

(S)-4-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-ylamino]benzonitrile;

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

(S)-N-[4-(3-ethoxypyrrolidine-1-yl)-2-methylinosine-7-yl]propionamide;

[4-(2-methoxypiperidine-1-yl)-2-methylinosine-7-yl]amide (S)-cyclopropanecarbonyl acids;

(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)amide, furan-2-carboxylic acid and

N-(2,6-dimethyl-4-pyrrolidin-1-rhinolin-7-yl)propionamide.

11. The method of obtaining the compounds according to one of claims 1 to 10, comprising the reaction of compounds of formula Ia in the presence of the compounds of formula XII with obtaining the compounds of formula I

where R1-R4and As defined in claim 1 and Hal represents chlorine, bromine or iodine.

12. The method of obtaining the compounds according to one of claims 1 to 10, comprising the reaction of compounds of formula Ib in the presence of one or both with the of dinani formula R 1-Hal and R2-Hal obtaining the compounds of formula I

where R1-R4and As defined in claim 1 and Hal represents chlorine, bromine or iodine.

13. The method of obtaining the compounds according to one of claims 1 to 10, comprising the reaction of compounds of formula Ic in the presence of at least one of the following compounds selected from R4-Hal, R4Sn(Bu)3, R4B(OH)2, LiR4and HalMgR4with obtaining the compounds of formula I

where R1-R4and As defined in claim 1 and Hal represents chlorine, bromine or iodine.

14. Compounds according to one of claims 1 to 10 for use as therapeutically active substances with selective antagonistic activity against receptor Y5 neuropeptides Y.

15. Compounds according to one of claims 1 to 10 to obtain drugs for the prevention and treatment of diseases that are caused by diseases associated with NPY receptor.

16. Pharmaceutical composition having selective antagonistic activity against receptor Y5 neuropeptides Y, including a connection according to one of claims 1 to 10 and a therapeutically inert carrier.

17. Method for the treatment and prevention of arthritis, cardiovascular diseases, diabetes, renal failure, eating disorders and obesity,which includes the introduction of an effective amount of a compound according to one of claims 1 to 10.

18. A method of treating obesity in a human in need of such treatment, which comprises administration to a human a therapeutically effective amount of a compound according to one of claims 1 to 10 and a therapeutically effective amount of a lipase inhibitor.

19. The method according to p, in which the lipase inhibitor is a orlistat.

20. The method according to p or 19 for simultaneous, separate or sequential administration.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

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

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

18 cl, 138 tbl, 527 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to novel pyrrole carboxylic acid amides or pyrrole thiocarboxylic acid amides of the formula (I): wherein X represents oxygen atom (O), sulfur atom (S); R1 represents -CF3- or -CF2H-group; R2 represents (C1-C3)-alkyl or (C1-C3)-alkoxy-(C1-C3)-alkyl; R3 represents hydrogen (H) or fluorine (F) atom; Q represents compounds of the formulas wherein R4 represents (C6-C14)-bicycloalkyl, (C6-C14)-bicycloalkenyl, (C6-C14)-bicycloalkadienyl, group of the formula: wherein R7, R8 and R9 represent independently of one another (C1-C3)-alkyl or (C1-C3)-halogenalkyl or group of the formula: wherein R10 and R11 represent H; R5 and R6 represent H. Compounds of the formula (I) can be used for protection of plants against infection with phytopathogenic fungi. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable properties of compounds.

20 cl, 4 sch, 8 tbl, 17 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, pharmacy.

SUBSTANCE: invention relates to novel derivatives of sulfonamide of the general formula (I): wherein A means a substitute chosen from 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) optionally substituted with 1 or 2 halogen atoms, (C1-C4)-alkyl or phenyl radical, or 5- or 6-membered heteroaryl radical comprising 1 or 2 atoms of O, N or S; bicyclic heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from O, N or S and optionally substituted with 1 or 2 halogen atoms or (C1-C4)-alkyl; R1 means hydrogen atom (H), (C1-C4)-alkyl, benzyl; n means 0, 1, 2, 3 or 4; R2 means -NRR5 or the group of the formula: wherein a dotted line means optional chemical bond; R, R4 and R5 mean independently H or (C1-C4)-alkyl; or one of its physiologically acceptable salts. Compounds of the formula (1) possess antagonistic activity with respect to serotonin HT6-receptors that allows their using in pharmaceutical composition and for preparing a medicament.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, chemical technology.

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

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

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

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

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

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel C-2'-methylated derivatives of paclitaxel of the formula (I): wherein R represents trifluoromethyl group, phenyl, 2-furyl, 2-thienyl; R1 represents tert.-butoxycarbonyl or benzoyl group; R2 represents hydroxy-group; R3 means hydrogen atom or in common with R2 forms residue of cyclic carbonate of the formula: under condition that when R3 means hydrogen atom then R is not phenyl. Also, invention relates to a pharmaceutical composition based on thereof and using for preparing medicinal agents possessing an antitumor activity. Invention provides preparing novel derivatives of paclitaxel that possess antitumor activity.

EFFECT: valuable medicinal property of derivatives and pharmaceutical composition.

4 cl, 1 tbl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

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

45 cl, 1 tbl, 57 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.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: 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

Up!