Derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole and their use as antidepressant agents

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole with common formula I where R1 is aryl or heteroaryl, aryl here being phenyl unsubstituted or substituted with F, Cl, O-alkyl or phenyl, whereas heteroaryl is pyridinyl or thyenyl, R2 designates H, SO2R3 or COR4 where R3 and R4 independently designate C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1- C6alkyl)aryl, heterocyclyl, carboxylate residues with 3-10 C-atoms, dimethylamide or NR5R6, C1-C10alkyl at that being methyl, propyl, butyl, butenyl, isobutyl, amyl, pent-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2OCH3, CH2O(CH2)2OCH3 or CH(benzyl)MSO2C6H4CH3, C3-C10cycloalkyl is cyclopropyl, cyclobutyl, cycloamyl, adamantane-1-yl, 2-phenylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-on-1-yl, (C1-C6alkyl)-C3-C10cycloalkyl is CH2-cycloamyl, (CH2)2-cycloamyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-on, aryl is phenyl, benzyl or naphthyl unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: phenyl, NO2, C1-C6alkyl, O-alkyl, CO2-alkyl, C(=O)C1-C6alkyl, CH2OC(=O)C6H5, F, Cl, Br, N(CH3)2, OCF3, CF3 or (C=O)CH3, (C1-C6alkyl)aryl is 3,4-dimethoxyphenyl-CH2, 4-chlorophenoxy-CH2, phenyl-CH=CH, benzyl-OCH2, phenyl-(CH2)2, 2-bromphenyl-CH2, 1-phenylpropyl, 2-chlorophenyl-CH=CH, 3-trifluorinemethylhenyl-CH=CH, phenoxy-CH2, phenoxy-(CH2)3 or phenoxy-CH(CH3), heterocyclyl is pyridinyl, isoxazole, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole or isoquinoline unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: Cl, C1-C6alkyl, phenyl, in their turn unsubstituted or mono- or polysubstituted with identical or different substitutes, namely: Cl or C1-C6alkyl, CF3, carboxylate residues with 3-10 C-atoms are CH3OC(=O)CH2, CH3OC(=O)(CH2)3, CH3CH2OC(=O)CH2, CH3CH2OC(=O)(CH2)2, CH3C(=O)OCH2, CH3C(=O)OC(CH3)2 or CH3C(=O)OCH(C6H5), and R5 and R6 independently designate H or aryl, aryl at that being benzyl or phenyl respectively mono- or polysubstituted with identical or different substitutes, namely: F, C1, O-alkyl, CN, CF3. Invention also relates to method of obtaining, to medicament and to use of compounds with common formula I.

EFFECT: obtaining of new biologically active compounds and medicinal agents based on the above formulas.

9 cl, 248 ex, 2 tbl

 

The present invention relates to substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole, to the way they are received, containing these compounds medicines, as well as the application of these substances to obtain drugs intended primarily for the treatment of depression and treatment of depression.

Depression is an emotional or mental disorder, mainly due to the depressive syndrome, manifested in a depressed mood, respectively, in melancholy mood, sadness, etc. Used for the treatment of depression, antidepressants are also important adjuvants in the treatment of pain (van Schayck and others, DFID, the 21st year of publication, No. 10, 1998, cc.304-313; Jung and others, J. Gen. Intern. Med. 12/6, 1997, cc.384-389; Onghena and Van Houdenhove, Pain 49, 1992, cc.205-219; Feuerstein, Der Schmerz 11, 1997, cc.213-226; Rowbotham, The Pain Medicine Journal Club 3/3, 1997, cc.119-122), primarily for chronic pain as a constant load on the body associated with pain can lead to depression (dysphoria) patients. Such dysphoria is particularly common in patients with cancer (Berard, Int. Med. Journ. 3/4, 1996, cc.257-259). Since to date there is no painkillers with clinically relevant antidepressant active components, in addition to used for the treatment of pain is th analgesics have to prescribe antidepressants. Since, however, suffering from chronic pain patients often need to take many different medicines, antidepressant in addition to pain relief results in an additional load on the body. For this reason, and to improve enforcement sick mode and regimens undoubted success could ensure that the analgesic active component with an antidepressant.

The basis of antidepressant action is suppression of serotonin reuptake.

Various substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole known from the literature. Common to them all is the use for the treatment of neuronal diseases.

The synthesis of substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole already described by Borg and others (Journ. Org. Chem. 60, 1995, cc.3112-3120), at the same time as the source material uses natural amino acids during synthesis carry out the dehydrogenation of diacylhydrazines, and describes the Brain and other (Synlett, No. 3, 2001, cc.382-384), while spending cyclodehydration 1,2-diacylhydrazines have in a microwave oven using agent dehydrogenation using polystyrene. In both these cases we are talking about solid-phase synthesis.

Another possibility for the synthesis pyrrolidinone or piperidinovyh derivatives, etc is naznacheniya for the treatment and prevention of neuronal diseases, as described in the application WO 01/04116.

In JP 2001-247569 also describes how to get pyrrolidinone or piperidinovyh derivatives and their use for the prevention and/or treatment of diseases involving the nervous disorders or neurodegenerative phenomena.

Based on the foregoing, the present invention was based on the task to offer effective analgesic substance of a new structural class, which, in addition, could be used for the treatment of depression and/or for anxiolysis.

According to the invention it has been unexpectedly found that substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula I have a pronounced antidepressant, and analgesic effect.

The object of the invention in accordance with this are substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula I

in which R1denotes aryl or heteroaryl,

R2denotes H, SO2R3or COR4where

R3and R4independently of one another denote C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1-C6alkyl)aryl, heterocyclyl, carboxylate residue with 3 to 10 C-atoms, dimethylamide or NR5R6where

R5and R6 independently of one another denote H or aryl.

In a preferred embodiment, the substituents in the compounds of formula I have the following values:

R1denotes aryl or heteroaryl, and the aryl is a phenyl, unsubstituted or substituted by an atom of F, Cl, O-alkyl or phenyl, and heteroaryl represents pyridinyl or thienyl,

R2denotes H, SO2R3or COR4where

R3and R4independently of one another denote C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1-C6alkyl)aryl, heterocyclyl, carboxylate residue with 3 to 10 C-atoms, dimethylamide or NR5R6while

C1-C10alkyl represents methyl, propyl, butyl, butenyl, isobutyl, pentyl, Penta-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2Och3CH2O(CH2)2OCH3or CH(benzyl)NSO2With6H4CH3,

With3-C10cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, adamantane-1-yl, 2-vinylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one-1-yl,

(C1-C6alkyl)-C3-C10cycloalkyl represents CH2-cyclopentyl, (CH2)2-cyclopentyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]hept is n-2-it, aryl represents phenyl, benzyl or naphthyl, unsubstituted or one-deputizing mnogozalny identical or different substituents, such as phenyl, NO2C1-C6the alkyl, S-atomic chain which may be interrupted by one or more heteroatoms from the group comprising N, O or S, preferably Oh, O-alkyl, CO2-alkyl, C(=O)1-C6the alkyl, CH2OC(=O)6H5, F, Cl, Br, N(CH3)2, OCF3, CF3, SCHF2SCF3or (C=O)CH3,

(C1-C6alkyl)aryl represents 3,4-acid-CH24 chlorphenoxy-CH2, phenyl-CH=CH, benzyl-co2, phenyl-(CH2)22-bromophenyl-CH21 is phenylpropyl, 2-chlorophenyl-CH=CH, 3-triptoreline-CH=CH, phenoxy-CH2phenoxy-(CH2)3or phenoxy-CH(CH3),

heterocyclyl represents pyridinyl, isoxazol, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole, or isoquinoline, unsubstituted or one-deputizing mnogozalny identical or different substituents, namely, Cl, C1-C6the alkyl, phenyl, in turn unsubstituted or one - or mnogosloinym identical or different substituents, namely, Cl or C1-C6the alkyl, CF3With(=O)CF3or SCH3,

carboxylate, ostatki 3-10 C-atoms are

CH3OS(=O)CH2CH3OS(=O)(CH2)3CH3CH2OC(=O)CH2,

CH3CH2OC(=O)(CH2)2CH3C(=O)och2CH3C(=O)OC(CH3)2or

CH3C(=O)och(C6H5), and

R5and R6independently of one another denote H or aryl, and the aryl represents benzyl or phenyl, respectively one or mnogozalny identical or different substituents, namely: F, Cl, O-alkyl, CN, CF3or OCF3.

Particularly preferred are the compounds of formula I, in which

R1denotes phenyl, biphenyl-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 2-forfinal, pyridine-3-yl, pyridine-4-yl or thiophene-2-yl,

R2denotes H, SO2R3or COR4where

R3and R4independently from each other represent CH3CH2OCO(CH2)2-, 2,4-acid, 2-chloropyridin-3-yl, 2-chloropyridin-4-yl, 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-it, 3-dimethylaminophenyl, 3,4-acid, 2,5-acid, 4-chlorophenyl, -CH(benzyl)HSO2With6H4CH3, 4,5-dichlorothiophene-2-yl, 2,4,6-trimetilfenil, 4-chlorphenoxamine, C6H5CH=CH-, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl, 2,4-differenl, 2,6-differenl, 4-bromophenyl, 4-ethoxyphenyl, 4-trifloromethyl, 2.5-bistrifluormethylbenzene, 1-phenyl-5-impregnated ሺ-1H-pyrazole-4-yl, 3-methoxyphenyl, 2-methyl-6-triptorelin-3-yl, 4-triftormetilfullerenov, 2,2,2-Cryptor-1-3,4-dihydro-1H-isoquinoline-2-ylatason or NR5R6where

R5and R6independently of one another denote H or 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2,5-acid, 2,5-dichlorophenyl, 2,5-differenl, 4-tormentil, 4-chloro-3-triptoreline, 4-trifloromethyl or 3-cyanophenyl.

Most preferred are the following substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole:

ethyl ester of 4-oxo-4-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl] butyric acid,

(2,4-acid)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

(2-chloropyridin-3-yl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

7,7-dimethyl-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfanilyl]bicyclo[2.2.1] heptane-2-it,

(3-dimethylaminophenyl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

2-(3,4-acid)-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl] alanon,

[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-chlorophenyl)methanon,

N-{1-benzyl-2-oxo-2-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]ethyl}-4-methylbenzenesulfonamide,

4-{5-[1-(4,5-dichlorothiophene-2-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine,

3-{5-[1-(2,5-dimethoxy tilsley)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine,

2-(2-forfinal)-5-[1-(2,4,6-trimethylbenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol,

2-(4-chlorophenoxy)-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon,

3-phenyl-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]propane,

(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

3-{5-[1-(2,4-differentiality)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine,

(4-bromophenyl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}mechanon,

(2-chloropyridin-4-yl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}mechanon,

(2,6-differenl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

(4-ethoxyphenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

3-{5-[1-(4-cryptomaterial)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine,

(2.5-bistrifluormethylbenzene)-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}mechanon,

(2.5-bistrifluormethylbenzene)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

(1-phenyl-5-propyl-1H-pyrazole-4-yl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

(2,3-differenl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}mechanon,

(2-methyl-6-triptorelin-3-yl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-trifloromethyl phenylphenyl)methanon,

2,2,2-Cryptor-1-{7-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfonyl]-3,4-dihydro-1H-isoquinoline-2-yl}Etalon,

1-{2-[5-(3-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-3-cyclopentylpropionic-1-he,

1-{2-[5-(3-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}pentane-1-it.

The terms "alkyl", "C1-C10alkyl" and "C1-C6alkyl" in the context of the present invention refers to an acyclic saturated or unsaturated hydrocarbon residues, which may be branched or straight chain, and may be unsubstituted or mono - or mnogosloinymi identical or different substituents and which contain (in the case of C1-C10of alkyl of 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), respectively (in the case of C1-C6of alkyl of 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) carbon atoms, i.e. C1-C10-, respectively, C1-C6alkaline group2-C10-, respectively, With2-C6alkeneamine group and2-C10-, respectively, With2-C6alkyline group. "Alkeneamine" groups have at least one double and "alkyline" group - at least one triple carbon-carbon bond. Preferably the alkyl is selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pen is Il, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, ethynyl (vinyl), ethinyl, propinyl (-CH2CH=CH2, -CH=CH-CH3-C(=CH2)-CH3), PROPYNYL (-CH2With≡CH,- ≡CH3), butenyl, butynyl, pentenyl, pentenyl, hexenyl, hexenyl, octenyl and octenyl. By "alkyl" in the context of the present description refers also remains formed From atoms of the chain which may be interrupted by one or more heteroatoms N, O or S, preferably an atom of O.

The term "C3-10cycloalkyl" (respectively "cycloalkyl") in the context of the present invention are indicated cyclic saturated or unsaturated hydrocarbon residues, which contain 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, each such residue may be unsubstituted or one-deputizing or mnogosloinym identical or different substituents, and optionally condensed with a benzene nucleus. In addition, such residues can also be a bi-, tri - or polycyclic ring system. As an example of cycloalkyl can be called cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and substituted and bicyclo[2.2.1]heptyl.

The term "aryl" in the context of the present invention refers to a residue that is selected from g is uppy, includes phenyl, naphthyl, phenanthrene, anthracene and biphenyl, and which may be unsubstituted or one-deputizing or mnogosloinym identical or different substituents. Preferably aryl is an unsubstituted or one-deputizing or mnogozalny identical or different substituents phenyl, 1-naphthyl or 2-naphthyl.

The term "heterocyclyl" refers to a monocyclic or polycyclic organic residue in which at least one cycle contains 1 heteroatom or 2, 3, 4 or 5 identical or different heteroatoms selected/selected from the group comprising N, O and S and which is saturated or unsaturated and unsubstituted or one-deputizing or mnogosloinym identical or different substituents. Examples heterocyclyl residues in the context of the present invention are monocyclic five-, six - or semicolonies organic residues with 1 heteroatom or 2, 3, 4 or 5 identical or different heteroatoms, which/which are nitrogen, oxygen and/or sulphur and condensed with a benzene core counterparts. A special subgroup heterocyclyl residues form a "heteroaryl" remains, by which we mean those heterocyclyl groups in which at least one cycle containing one or more heteroatoms, I what is heteroaromatic. Each such heteroaryl residue may be unsubstituted or one-deputizing or mnogosloinym identical or different substituents. As an example heterocyclyl residues in the context of the present invention can be called pyrrolidinyl and morpholinyl. Examples of heteroaryl residues are pyrrolyl, furanyl, thienyl, thiadiazolyl, triazolyl, isoxazolyl, isoquinoline, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl and oxadiazolyl and their condensed with a benzene nucleus analogues (for example, benzoxadiazole). Each of these residues can be represented in unsubstituted or substituted.

The terms "(1-C6alkyl)-C3-C10cycloalkyl" and "(1-C6alkyl)aryl" in the context of the present invention refers to groups in which cycloalkenyl, respectively aryl residue via C1-C6alkyl group linked to a substituted their connection.

In the context of the present invention, the term "substituted"used in respect of "alkyl", "alkenyl", "alkenyl", "quinil" and "cycloalkyl"means single or multiple substitution of one or several hydrogen atoms, for example, atom (F, Cl, Br, I, group-CN, NH2, NH-alkyl, NH-aryl, NH-alkylaryl, NH-heterocyclyl, N(alkyl)2N(al what Ilarion) 2N-alkyl-N-aryl, a group of NO2HE, geography, O-alkyl, O-aryl, O-alkylaryl, C(=O)1-C6the alkyl, C(=O)aryl, C(=O)1-C6alkylaryl, C(=O)-heterocyclyl, a group of CO2N, CO2-alkyl, CO2-alkylaryl, group C(=O)NH2With(=O)NH-alkyl, C(=O)NH-aryl, C(=O)NH-heterocyclyl, C(=O)N(alkyl)2With(=O)N(alkylaryl)2, cycloalkyl, aryl or heterocyclyl, under mnogosloinymi refers to the remnants of the remnants of that mnogozalny, such as bilateral or transamidase, either on different or on the same atoms. When multiple substitution, the substituents may be identical or different. In addition, it is also possible substitution of the sulfonamide.

In the context of the present invention the term "substituted"used in respect to "aryl", "heterocyclyl"and "heteroaryl"means single or multiple, for example two, three or four times, substitution of one or more hydrogen atoms of the ring system is an acceptable substitute. If the values of such acceptable surrogates "aryl", "heterocyclyl" and "heteroaryl" is not specifically mentioned in any place of this description or in the claims, such substituents include an atom of F, Cl, Br, I, group-CN, NH2, NH-alkyl, NH-aryl, NH-alkylaryl, NH-heterocyclyl, N(alkyl) 2N(alkylaryl)2the group NO2, SH, S-alkyl, OH, O-alkyl, O-cycloalkyl, O-aryl, O-alkylaryl, heterocyclyl, group, CHO, C(=O)C1-C6alkyl, C(=O)CF3C(=O)aryl, C(=O)C1-C6alkylaryl, a group of CO2H, CO2-alkyl, CO2-alkylaryl, group C(=O)NH2C(=O)NH-alkyl, C(=O)NH-aryl, C(=O)NH-heterocyclyl, C(=O)N(alkyl)2the group SO2NH2, SO3H, CF3, CHF2CH2F, OCF3, OCHF2, OCH2F, SCF3, SCHF2, SCH2F, alkyl, cycloalkyl, aryl and/or heterocyclyl, and the substitution may be one or, under certain conditions on different atoms (and Deputy under certain conditions, in turn, can also be substituted). When multiple substitution of the substituents, in addition, may be identical or different. The most preferred substituents of "aryl" and "heterocyclyl are C1-C6alkyl, F, Cl, Br, I, CF3, O-alkyl, OCF3, phenyl, CN and/or NO2.

The expression "condensed with the benzene nucleus in the context of the present invention means that the benzene ring condensed with another cycle.

Another object of the invention is a method for substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula I.

The proposed invention in connection receive in accordance with the following the th of the synthesis scheme:

To obtain the proposed invention substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole BOC-Proline is subjected to interaction with etelcharge.com and hydrazine in an appropriate solvent, such as THF (tetrahydrofuran). The resulting hydrazide interaction with the corresponding acid chloride of the acid in a solvent such as THF, in turn diacylhydrazine. For ring closure (cyclization) diacylhydrazine mixed with the appropriate acid and dehydrating reagent, for example with P2O5CH3SO3N, pyridine and/or SOCl2. After ring closure protective group otscheplaut and the product is subjected to interaction with the corresponding acid chloride acid or isocyanate obtaining in this way compounds of General formula I according to the invention.

Proposed in the invention substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula I toxicologically harmless and therefore suitable as pharmaceutical active substances for use in pharmaceutical products.

Another object of the present invention in accordance with this drugs are those containing at least one proposed in the invention substituted derivative 2-pyrrolidin-2-yl-[1,3,4]oxadiazole total is ormula I, and optionally physiologically compatible auxiliary substances.

Preferably proposed in the invention of medicines designed to fight the pain and for the treatment or prevention of depression, urinary incontinence, diarrhea, pruritus, alcohol, drug and/or medicament addiction, nausea and vomiting, for anxiolysis, increasing vigilante and/or enhance libido.

The object of the present invention is also the use of at least one substituted derivative 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula I to obtain medicines designed to combat the pain and for the treatment or prevention of depression, urinary incontinence, diarrhea, pruritus, alcohol, drug and/or medicament addiction, nausea and vomiting, for anxiolysis, increasing vigilante and/or enhance libido.

The invention relates further to a method of treatment of depression, namely, that use of the compounds according to the invention.

Proposed in the invention medicines can be represented and used in the form of liquid, semi-solid or solid dosage forms, for example in the form of solutions for injection, drops, mixtures, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, Primate is, gels, emulsions, aerosols or in loose powder form, for example, in the form of small spherical particles (pellets or granules.

Proposed in the invention medicines along at least one proposed in the invention substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula (I usually also contain a physiologically compatible pharmaceutical auxiliary substances, preferably selected from the group including carriers, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrating agents, slip agents, lubricants, aromas and binders.

The choice of physiologically compatible auxiliary substances, as well as applied their number depend on whether the drug for oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, nasal, buccal, rectal or topical application, for example, for application to infected areas of the skin, mucous membranes, or for introduction into the affected eye. For oral administration suitable, in particular, the dosage form as tablets, pills, capsules, granules, pellets, drops, medicines and syrups, and for parenteral, local and Inga is anionnogo use suitable solutions suspension, easily recoverable dry compositions, as well as sprays. Proposed in the invention compounds of General formula I in depot form, in dissolved form or embedded in a plaster, optionally with the addition of promote penetration through the skin of funds, also suitable for percutaneous introduction. Intended for oral or percutaneous administration of medicinal forms may also be a retard forms, which provide a slow release proposed in the invention compounds of General formula I.

Proposed in the invention medicines and pharmaceutical compositions obtained using well-known technology of preparation of medicines means, devices, methods, and methods described, for example, in "Remington''s Pharmaceutical Sciences", edited by A.R. Gennaro, 17th ed., published by Mack Publishing Company, Easton, Pa., 1985, first of all in section 8, Chapter 76-93. The publication specified in this part are included in the present description by reference.

Assigned patient number corresponding proposed in the invention compounds of General formula I can vary within certain limits and depends, for example, on the weight and age of the patient and on the route of administration, indications for use and the severity of the disease. Usually at least one offer in sobretensiones derived 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula I are introduced into the organism in dosage, part of 0.005 to 500 mg per kg of body weight of the patient, preferably from 0.05 to 5 mg per kg of body weight.

Proposed in the present invention the connection though fall under the General formula in JP 2001-247569, but in no way highlighted in this publication as a special and not related to the preferred compounds. Described in the publication compounds expected to be used for the elongation of nerve fibres and, therefore, be used for the treatment and/or prevention of disorders of the nervous system associated with diabetes, neuropathy, neurotomy, diseases caused by destruction of the nerve, such as ABS (amyotrophic lateral sclerosis or multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Horai or spinal cord injuries.

In contrast, the authors of this application has failed to prove that the proposed invention is effective analgesic compounds also possess pronounced anti-depressive effect.

Examples

Example No.Proposed in the invention, the connection
14-{5-[1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
2ethyl ester of 3-oxo-3-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin the-1-yl]propionic acid
34-{5-[1-(2,4,6-trimethylbenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4] oxadiazol-2-yl} pyridine
4ethyl ester of 4-oxo-4-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]butyric acid
5(2,4-acid)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
6(2-chloropyridin-3-yl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl] metano
77,7-dimethyl-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfanilyl]bicyclo[2.2.1 ]heptane-2-he
81-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]butane-1-he
9[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-methoxyphenyl)metano
102-[1-(3-chloro-4-perpenicular)pyrrolidin-2-yl]-5-thiophene-2-yl-[1,3,4]oxadiazol
11[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
12(3-dimethylaminophenyl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
132-(3,4-acid)-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon
14[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol the-2-yl)pyrrolidin-1-yl]-(4-chlorophenyl)metano
154-{5-[1-(4-chlorobenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
164-{5-[1-(4-methoxybenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
17isoxazol-5-yl-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
184-{5-[1-(butane-1-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine

Example No.Proposed in the invention, the connection
192-(2-methoxyethoxy)-1-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}alanon
20cyclobutyl-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
21N-{1-benzyl-2-oxo-2-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]ethyl}-4-methylbenzenesulfonamide
224-{5-[1-(4,5-dichlorothiophene-2-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
231-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon
241-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-2-methoxyethanol
25(2-chloropyridin-4-yl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
26[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(3,4,5-trimethoxy enyl)metano
27(4-bromophenyl)-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl} metano
28methyl ester 5-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-5-oxovalerate acid
29[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]metano
303-{5-[1-(2,5-dimethoxyphenylacetone)pyrrolidin-2-yl] -[1,3,4]oxadiazol-2-yl}pyridine
31(2-methylsulfinylphenyl-3-yl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
322-phenyl-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl] ethane he
33ethyl ester of 3-oxo-3-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]propionic acid
34(3-dimethylaminophenyl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl} metano
352-oxo-2-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]ethyl ester of acetic acid
36(4-ethoxyphenyl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
372-(2,5-acid)-1-[2-(5-what iridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon
38methyl ester of 3-oxo-3-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]propionic acid
39(2-ethoxyphenyl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
403-[5-(1-phenylmethanesulfonyl-2-yl)-[1,3,4]oxadiazol-2-yl]pyridine
41dimethylamide 2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfonic acid

Example No.Proposed in the invention, the connection
424,7,7-trimethyl-1 -[2-(5-phenyl-[ 1,3,4]oxadiazol-2-yl)pyrrolidin-1-carbonyl]-2-oxabicyclo[2.2.1]heptane-3-one
43{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(4-trifloromethyl)metano
44[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]thiophene-2-ylmethanol
45[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-o-trimeton
461-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-2-methoxyethanol
47methyl ester 5-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-5-oxovalerate acid
48methyl ester of 3-{2-[-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-3-oxopropanoic acid
49biphenyl-4-yl-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
50(2-chlorophenyl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
51(2-chloropyridin-3-yl)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
521-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]butane-1-he
531,1-dimethyl-2-oxo-2-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl] ethyl ester of acetic acid
54[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-n-trimeton
55(2,3-dimetilfenil)-[2-(5-pyridin-3-yl-[1,3,4] oxadiazol-2-yl)pyrrolidin-1-yl]metano
562-cyclopentyl-1-[2-(5-pyridin-4-yl-[1,3,4] oxadiazol-2-yl)pyrrolidin-1-yl]alanon
573-{5-[1-(3-chlorobenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
581-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}pentane-1-he
591-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-carbonyl}-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one
60adamantane-1-yl-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
61 2-(2-forfinal)-5-[1-(2,4,6-trimethylbenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol
62[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(2-triptoreline)metano
632-[1-(3,4-dimethoxybenzenesulfonamide)pyrrolidin-2-yl]-5-(2-forfinal)-[1,3,4]oxadiazol
642-oxo-1-phenyl-2-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]ethyl ester of acetic acid

Example No.Proposed in the invention, the connection
65furan-2-yl-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
66(4-bromophenyl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
672-(4-chlorophenoxy)-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon
684-[5-(1-benzisothiazolin-2-yl)-[1,3,4]oxadiazol-2-yl]pyridine
69furan-2-yl-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
701-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}Penta-4-EN-1-he
713-{5-[1-(2-chlorobenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
72 4-{5-[1-(5-chlorothiophene-2-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
73[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
74(5-methylisoxazol-3-yl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
75{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}pentacarbonyliron
76ethyl ester of 4-oxo-4-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl] butyric acid
772-(3-methoxyphenyl)-5-[1-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol
784-{5-[1-(2,3,5,6-tetramethylbutylphenol)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
791-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]hexane-1-he
80cyclopentyl-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
81(3-chloro-2-forfinal)-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
822-[1-(4-chloro-2,5-dimethylbenzenesulfonyl)pyrrolidin-2-yl]-5-(4-chlorophenyl)-[1,3,4]oxadiazol
83(4-chlorophenyl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-ylmethanone
843-phenyl-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]propenone
85(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
863-{5-[1-(2,4-differentiality)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl} pyridine
872-benzyloxy-1-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}alanon

Example No.Proposed in the invention, the connection
88(6-chloropyridin-3-yl)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
893,3-dimethyl-1-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]butane-1-he
90(2-ethoxyphenyl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
91(4-ethylphenyl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
92(4-bromophenyl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
93(5-methylisoxazol-3-yl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
94(2-chloropyridin-4-yl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin the-1-yl}metano
95{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(4-nitrophenyl)metano
961-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-3-phenylpropane-1-he
97(3-chlorothiophene-2-yl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
982-(2-forfinal)-5-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol
994-{5-[1-(4-butoxybenzoyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
100cyclopropyl-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
101(2,6-differenl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
102(2.5-dimethylfuran-3-yl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
103methyl ester 2-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfonyl]benzoic acid
1042-ethyl-1-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]butane-1-he
105(3-diftormetilirovaniya)-[2-(5-pyridin-4-yl-[1,3,4] oxadiazol-2-yl)pyrrolidin-1-yl]methane
106benzo[1,2,5]oxadiazol-5-yl-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-ylmethanone
1073-{5-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
1084-{5-[1-(3-triftormetilfullerenov)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
109(4-ethoxyphenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1102-(2-bromophenyl)-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon

Example No.Proposed in the invention, the connection
111[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-triptoreline)metano
1122-thiophene-2-yl-5-[1-(2,4,6-trimethylbenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol
1131-{4-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfonyl]phenyl}alanon
114furan-2-yl-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
115(3,5-differenl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
116[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-nitrophenyl)metano
117(4-forfinal)-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(4-propylphenyl)metano
119(3,4-differenl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
120(5-fluoro-2-triptoreline)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1212-phenyl-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon
122[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(3-trifloromethyl)metano
123(4-forfinal)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
124(4-propylphenyl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1252-phenyl-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]butane-1-he
126[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-trifloromethyl)metano
127(3-nitrophenyl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1282-ethyl-1-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}butane-1-he
129(5-fluoro-2-triptoreline)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1301-{2-[5-(2-FPO is phenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-2-propylpentyl-1-he
131{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl)methanon
132[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(2-triptoreline)metano
1332-(3-methoxyphenyl)-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon

Example No.Proposed in the invention, the connection
1343-{5-[1-(4-cryptomaterial)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
135{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}furan-2-ylmethanol
136{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}furan-2-ylmethanol
137(4-methyl-3-nitrophenyl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
138(4-methoxyphenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
139(2-chloropyridin-4-yl)-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
140(3-bromophenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1412-propyl-1-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]p is ntan-1-he
1422-(4-chlorophenyl)-5-{1-[4-(1,1-dimethylpropyl)benzylmethyl]pyrrolidin-2-yl}-[1,3,4]oxadiazol
143(3-chlorophenyl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
144(3-chloro-4-forfinal)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
145(2,6-debtor-3-were)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
146(3-fluoro-4-were)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
147{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(4-methyl-[1,2,3]thiadiazole-5-yl)methanon
1482-thiophene-2-yl-5-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol
149{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(3,4-acid)metano
150{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(4-ethylphenyl)metano
151(4-tert-butylphenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
152the naphthas-1-yl-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1531-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]Penta-4-EN-1-he
15 {2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(4-propylphenyl)metano
1551-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-3-phenylpropane

Example No.Proposed in the invention, the connection
1561-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-3,3-dimethylbutan-1-he
1572-[1-(4-chlorobenzenesulfonyl)pyrrolidin-2-yl]-5-(4-chlorophenyl)-[1,3,4]oxadiazol
158adamantane-1-yl-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
159{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-o-trimeton
160benzo[1,2,5]oxadiazol-5-yl-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
161(4-nitrophenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1623-(2-chlorophenyl)-1-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl] pyrrolidin-1-yl}propenone
1634-{5-[1-(4-ethylbenzyltoluidines)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine
164(2.5-bistrifluormethylbenzene)-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
165(2,5-is scriptinterface)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
166(1-phenyl-5-propyl-1H-pyrazole-4-yl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1671-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-3-(3-triptoreline)propane
168(2-methylsulfinylphenyl-3-yl)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
169(2.5-dimethylfuran-3-yl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
170{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(5-fluoro-2-triptoreline)metano
171(3-chlorophenyl)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
172(4-chlorophenyl)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
173(2,3-differenl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
174(2-methyl-6-triptorelin-3-yl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1751-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-2-ethylbutane-1-he
1761-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}Penta-4-EN-1-he
177[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrol the DIN-1-yl]pentacarbonyliron
178(3-fluoro-4-triptoreline)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano

tr> (5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
Example No.Proposed in the invention, the connection
1791-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-4-phenoxybutyl-1-he
180[1-(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-yl]-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
181[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-triftormetilfullerenov)metano
1822,2,2-Cryptor-1-{7-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfonyl]-3,4-dihydro-1H-isoquinoline-2-yl}alanon
1831-[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-2-methoxyethanol
184(2-chloro-5-triptoreline)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
185(2-chloro-5-triptoreline)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1861-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-2-phenoxyethane
187(2,3-debtor-4-were)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
188methyl ester 2-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfonyl]benzoic acid
1892-biphenyl-4-yl-5-{1-[4-(1,1-dimethylpropyl)benzylmethyl]pyrrolidin-2-yl}-[1,3,4]oxadiazol
1903-cyclopentyl-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]propane-1-he
1913,3-dimethyl-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]butane-1-he
192(2-chloro-4-nitrophenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1931-[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-2-(2-methoxyethoxy)alanon
1941-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-2-ethylhexan-1-he
1951-[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-2-phenylbut-1-he
196(2,3-dimetilfenil)-{2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
197(2.5-bistrifluormethylbenzene)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
1982-(4-chlorophenoxy)-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon
199(2-ethoxyphenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
200

Example No.Proposed in the invention, the connection
201(4-methyl-[1,2,3]thiadiazole-5-yl)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
202[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(3,4-dichlorophenyl)metano
203(4-propylphenyl)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
204(3,4-differenl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
205(3-chloro-2-forfinal)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
206(2-chlorophenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
207[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-m-trimeton
2081-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}butane-1-he
209{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}pyridine-2-ylmethanol
210[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-triptoreline)metano
2112-biphenyl-yl-5-[1-(4-chlorobenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol
2121-[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-2-phenoxyethane
2132-phenyl-5-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol
214[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(3-trifloromethyl)metano
215[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-propylphenyl)metano
2162-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carbonyl]benzyl ester of benzoic acid
217{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(4-nitrophenyl)metano
2182 phenoxy-1-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]propane-1-he
2192-(4-chlorophenyl)-1-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon
220[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(2-chloro-5-triptoreline)metano
221(2,3-differenl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
2222-biphenyl-4-yl-5-[1-(3-chloro-4-perpenicular)pyrrolidin-2-yl]-[1,3,4]oxadiazol
223(3,4-differenl)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano

Example No.Proposed in the invention, the connection
2241-[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-2-propylpentyl-1-he
225(3-fluoro-4-triptoreline)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
226(6-chloro-2-fluoro-3-were)-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
227(2-vinylcyclopropyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
228(4-bromo-3-were)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano
229[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(2,3-dimetilfenil)metano
230[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(3-chlorophenyl)metano
231[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(2,3-debtor-4-were)metano
232(2-chloro-6-forfinal)-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}metano
233[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)methanon
234{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-(2,3-dichlorophenyl)metano
235(4-ethoxyphenyl)amide 2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carboxylic acid
236(2,5-dichlorophenyl)amide 2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carboxylic acid
2374-forbindelse 2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-carboxylic acid
238(2,5-acid)amide 2-[5-(2-forfinal)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-carboxylic acid
239(2,5-acid)amide 2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carboxylic acid
240(2.5-differenl)amide 2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carboxylic acid
241(3-cyanophenyl)amide 2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carboxylic acid
242(3-cyanophenyl)amide 2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carboxylic acid
243(3-cyanophenyl)amide 2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-carboxylic acid
244(4-chloro-3-triptoreline)amide 2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carboxylic acid
245(4-methoxyphenyl)amide 2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carbon is Oh acid
246(4-trifloromethyl)amid-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-carboxylic acid

Example No.Proposed in the invention, the connection
2471-{2-[5-(3-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-3-cyclopentylpropionic-1-he
2481-{2-[5-(3-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}pentane-1-he

Proposed in the invention compounds were obtained by the methods described above while below them the more detail is illustrated on two examples.

Example 247

1-{2-[5-(3-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-3-cyclopentylpropionic-1-he

Stage 1

The solution ethylchloride (10,33 ml) in 20 ml of dry THF was added dropwise over 5 min to a stirred and cooled to -15°With the solution of the BOC-(L)-Proline (23.7 g) and 15,07 ml of triethylamine in 250 ml of dry THF. Next was stirred for further 30 min at -15°C. the Cold reaction mixture was filtered, the filtrate was concentrated to a volume of about 125 ml, and then for 15 min was added dropwise to a stirred and cooled to 0°With a solution of hydrazine monohydrate (10.5 ml) in 150 ml dry THF. The reaction mixture was stirred during the next 15 min at 0° With and then for 2 h at room temperature. Then the solution was separated by decantation through the bottom of the flask from the petty-white oil and concentrated to dryness. The crude product without further purification was used in the next stage. The output was 25,63,

Stage 2

11,42 ml 3-chlorobenzylchloride in 10 ml of dry THF over 5 min was added dropwise to a stirred and cooled to -15°With the solution of the hydrazide b (18.6 g) and triethylamine (13 ml) in 180 ml dry THF. Next was stirred for 20 min at -15°C, for 60 min at 0°and for 2 h at room temperature. Then the reaction mixture was filtered and the filtrate was concentrated to dryness. The oily crude brown product was purified by chromatography on silica gel (DHM, 3.75% of methanol). The output was 18,67,

Stage 3

The cyclization was carried out in anhydrous diethyl ether in a nitrogen atmosphere. 6.3 g SOCl2was added dropwise to a cooled to 0°With the solution of the hydrazide (15 g) and 8.4 g of pyridine in dry diethyl ether. The reaction mixture was stirred for 2 h at 0°C. the Resulting salt was filtered and the filtrate was concentrated at 0°C. the Residue was dissolved in 500 ml of toluene in a nitrogen atmosphere was heated under reflux. After 2 h, the solution koncentrirane and dryness and purified by chromatography on silica gel (diethyl ether). The output was 13,

Stage 4

13 g derived oxadiazole d was dissolved in 25 ml DHM (dichloromethane). After adding 5 ml triperoxonane acid (TFA) was stirred for 6 days in a nitrogen atmosphere. After adding 10 ml triperoxonane acid, stirring was continued for 6 h, after which the reaction mixture was concentrated to dryness. It was further added 100 ml of a saturated aqueous solution of NaHCO3and 100 ml DHM and the aqueous phase is twice were extracted using DHM. The combined organic phases were dried over Na2SO4and concentrated to dryness. Product without further purification was used in the next stage. The output was 10,

Stage 5

804 mg derived oxadiazole e was dissolved in 9 ml DHM. At -20°With added 326 mg of triethylamine and 517 mg 3-cyclopentylpropionate in 1 ml DHM. The reaction mixture was stirred for 2 h at -20°and then concentrated to dryness. The product was purified by chromatography on a column (silica gel, ethyl acetate/heptane 1:2, then the basic alumina, ethyl acetate/heptane 1:2). The output was 170 mg

Example 248

1-{2-[5-(3-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}pentane-1-he

Stage 1-4 similar stages 1-4 in example 247.

Stage 5

<>

1.3 g of the derived oxadiazole e was dissolved in 9 ml DHM. At -20°added 1 g of triethylamine and 620 mg of 3-valerylchloride in 1 ml DHM. The reaction mixture was stirred for 2 h at -20°and then concentrated to dryness. The product was purified by chromatography on a column (silica gel, ethyl acetate/heptane 1:2, then the basic alumina, ethyl acetate/heptane 1:2). The output was 181 mg

Pharmacological studies

Studies on the inhibition of serotonin reuptake (NT)

To conduct these studies in vitro using freshly isolated from the relevant departments of rat brain of synaptosome. In each case use the so-called "P2"is the fraction that dissect in accordance with the recommendations described in Gray and Whittaker (E.G.Gray and V.P.Whittaker, Journ. Anat. 76, 1962, cc.79-88). To capture NT these vesicular particles are separated from the medulla oblongata and the bridge brain of male rats. A detailed description of this methodology can be found in the literature (M.Ch.Frink, H.-H.Hennies, W.Englberger, M.Haurand and .Wilffert, Arzneim. - Forsch./Drug Res. 46 (III), 11, 1996, cc.1029-1036).

The table below presents the results obtained when testing some compounds on the inhibition of their capture NT.

Table 1
Compound of example No.Capture NT, % inhibition
472
581
684
764
1254
1367
1469
2153
2260
3060
6150
6750
8461
8561
8673
9258
9450
10154
10954
13455
16480
16576
16678
17362
17461
18162
18252

Tests of analgesia in mice in the test for pain

Study of the analgesic efficacy was performed on mice, tracking their behavioural response in the test for pain is Indra, induced familienaam (modified method described in I.C.Hendershot and J.Forsaith, see Journ. Pharmacol. Exp. Ther. 125, 1959, cc.237-240). For these purposes, used male mouse strain NMRI weighing 25-30 g Groups of 10 animals each, were selected for a single dose of the test compounds in 10 min after intravenous injection of such compounds were administered intraperitoneally injected at a dose of 0.3 ml/mouse of a 0.02%aqueous solution of finishinga (phenylbenzophenone, the company Sigma, Deisenhofen; preparation of the solution: the addition of 5% ethanol and the extract in a water bath at 45°). Experimental animals were placed singly in a special cell for observation. Using a push-button counter in intervals from 5 to 20 minutes after administration of finishinga counted the number of induced pain extensor movements (so-called behavioral response to pain: in this case, the bowing of the body with stretching of the hind limbs). As control served as the animals, which were injected with only saline solution of sodium chloride. All compounds were tested in a standard dose of 10 mg/kg Expressed as a percentage degree of inhibition (% inhibition) reaction to pain as a result of introduction of the respective compounds was calculated by the following formula:

Some connections with the neighbors dependent on their dosage reducing the number of responses to pain compared with the levels in studied in parallel experiments, control groups, which was introduced finishined, through regression analysis (processing program Martens EDV Service, Eckental) was calculated ED50-values for these reactions to pain with trust region 95%.

Used in the research proposed in the invention compounds showed pronounced analgesic efficacy. The results are presented in the table below.

Table 2
ExampleExpressed as % inhibition of the response to pain syndrome with intravenous test compounds at a dose of 10 mg/kg
24733
24845

1. Substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula I

in which R1denotes aryl or heteroaryl, and the aryl is a phenyl, unsubstituted or substituted by F, Cl, O-alkyl or phenyl, and heteroaryl represents pyridinyl or thienyl,

R2denotes H, SO2R3or COR4where

R3and R4independently of one another denote C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl (C 1-C6alkyl)aryl, heterocyclyl, carboxylate residue with 3 to 10 C-atoms, dimethylamide or NR5R6while

C1-C10alkyl represents methyl, propyl, butyl, butenyl, isobutyl, pentyl, Penta-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2Och3CH2O(CH2)2OCH3or CH(benzyl)NSO2With6H4CH3,

With3-C10cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, adamantane-1-yl, 2-vinylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one-1-yl,

(C1-C6alkyl)-C3-C10cycloalkyl represents CH2-cyclopentyl, (CH2)2-cyclopentyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-it, aryl represents phenyl, benzyl or naphthyl, unsubstituted or one-deputizing mnogozalny identical or different substituents, and phenyl, NO2With1-C6the alkyl, O-alkyl, CO2-alkyl, C(=O)1-C6the alkyl, CH2OC(=O)6H5, F, Cl, Br, N(CH3)2, OCF3, CF3or (C=O)CH3,

(C1-C6alkyl)aryl represents 3,4-acid-CH24 chlorphenoxy-CH2, phenyl-CH=CH, benzyl-co2, phenyl-(CH2)22-bromophenyl-CH21 is phenylpropyl, 2-chlorophenyl-the N=CH, 3-triptoreline-CH=CH, phenoxy-CH2phenoxy-(CH2)3or phenoxy-CH(CH3),

heterocyclyl represents pyridinyl, isoxazol, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole, or isoquinoline, unsubstituted or one-deputizing mnogozalny identical or different substituents, namely Cl, C1-C6the alkyl, phenyl, in turn unsubstituted or one - or mnogosloinym identical or different substituents, namely Cl or C1-C6the alkyl, CF3,

carboxylate residues with 3-10 C-atoms represent CH3OS(=O)CH2CH3OS(=O)(CH2)3CH3CH2OC(=O)CH2CH3CH2OC(=O)(CH2)2CH3C(=O)OCH2CH3C(=O)OC(CH3)2or CH3C(=O)och(C6H5), and

R5and R6independently of one another denote H or aryl, and the aryl represents benzyl or phenyl, respectively one or mnogozalny identical or different substituents, namely, F, Cl, O-alkyl, CN, CF3.

2. Compounds according to claim 1, characterized in that

R1denotes phenyl, biphenyl-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 2-forfinal, pyridine-3-yl, pyridine-4-yl or thiophene-2-yl,

R2denotes H, SO2R3or COR 4where

R3and R4independently from each other represent CH3CH2OCO(CH2)2-, 2,4-acid, 2-chloropyridin-3-yl, 2-chloropyridin-4-yl, 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-it, 3-dimethylaminophenyl, 3,4-acid, 2,5-acid, 4-chlorophenyl,

-CH(benzyl)NSO2With6H4CH3, 4,5-dichlorothiophene-2-yl, 2,4,6-trimetilfenil, 4-chlorphenoxamine,6H5CH=CH-, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl, 2,4-differenl, 2,6-differenl, 4-bromophenyl, 4-ethoxyphenyl, 4-trifloromethyl, 2.5-bistrifluormethylbenzene, 1-phenyl-5-propyl-1H-pyrazole-4-yl, 3-methoxyphenyl, 2-methyl-6-triptorelin-3-yl, 4-triftormetilfullerenov, 2,2,2-Cryptor-1-3,4-dihydro-1H-isoquinoline-2-ylatason or NR5R6where

R5and R6independently of one another denote H or 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2,5-acid, 2,5-dichlorophenyl, 2,5-differenl, 4-tormentil, 4-chloro-3-triptoreline, 4-trifloromethyl or 3-cyanophenyl.

3. Substituted derivative 2-pyrrolidin-2-yl-[1,3,4]oxadiazole from the group including

ethyl ester of 4-oxo-4-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]butyric acid,

(2,4-acid)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

(2-chloropyridin-3-yl)-[2-(5-pyridin-4-yl-[1,3,4]oxadi the evils-2-yl)pyrrolidin-1-yl]metano,

7,7-dimethyl-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfanilyl]bicyclo[2.2.1]heptane-2-it,

(3-dimethylaminophenyl)-[2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

2-(3,4-acid)-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon,

[2-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-chlorophenyl)methanon,

N-{1-benzyl-2-oxo-2-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]ethyl}-4-methylbenzenesulfonamide,

4-{5-[1-(4,5-dichlorothiophene-2-sulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine,

3-{5-[1-(2,5-dimethoxyphenylacetone)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine,

2-(2-forfinal)-5-[1-(2,4,6-trimethylbenzenesulfonyl)pyrrolidin-2-yl]-[1,3,4]oxadiazol,

2-(4-chlorophenoxy)-1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]alanon,

3-phenyl-1-[2-(5-phenyl-[1,3,4] oxadiazol-2-yl)pyrrolidin-1-yl]propane,

(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-yl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

3-{5-[1-(2,4-differentiality)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine,

(4-bromophenyl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-yl]pyrrolidin-1-yl}mechanon,

(2-chloropyridin-4-yl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}mechanon,

(2,6-differenl)-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)p is Raiden-1-yl]metano,

(4-ethoxyphenyl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

3-{5-[1-(4-cryptomaterial)pyrrolidin-2-yl]-[1,3,4]oxadiazol-2-yl}pyridine,

(2.5-bistrifluormethylbenzene)-{2-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}mechanon,

(2.5-bistrifluormethylbenzene)-[2-(5-thiophene-2-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

(1-phenyl-5-propyl-1H-pyrazole-4-yl)-[2-(5-pyridin-3-yl[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

(2,3-differenl)-{2-[5-(3-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl)methanon,

(2-methyl-6-triptorelin-3-yl)-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]metano,

[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-yl]-(4-triftormetilfullerenov)methanon,

2,2,2-Cryptor-1-{7-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)pyrrolidin-1-sulfonyl]-3,4-dihydro-1H-isoquinoline-2-yl}Etalon,

1-{2-[5-(3-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}-3-cyclopentylpropionic-1-he,

1-{2-[5-(3-chlorophenyl)-[1,3,4]oxadiazol-2-yl]pyrrolidin-1-yl}pentane-1-it.

4. The method of obtaining substituted derivatives of 2-pyrrolidin-2-yl-[1,3,4]oxadiazole General formula I

where R1and R2have the meanings defined in claim 1, including the interaction of the compounds of formula II

is the ethyl formate and hydrazine in an appropriate solvent, obtaining the compounds of formula III

the compound of formula III is subjected to interaction with the corresponding acid chloride of the acid in the solvent, obtaining diacylhydrazine formula IV

the compound of formula IV to a ring closure is mixed with the appropriate acid and dehydrating reagent to obtain the compounds of formula V

where R1matter defined in claim 1,

then otscheplaut protective group to obtain the compounds of formula VI

and the compound of formula VI is subjected to interaction with the corresponding acid chloride acid or isocyanate to obtain the compounds of formula I.

5. Drug with antidepressant and analgesic action, containing as active ingredient at least one compound of General formula I according to one of claims 1 to 3, and optionally physiologically compatible auxiliary substances.

6. The drug according to claim 5 for dealing with pain.

7. The drug according to claim 5 for the treatment or prevention of depression.

8. Applying at least one of the compounds of General formula I according to one of claims 1 to 3 to obtain the medication is tion means, designed to combat the pain.

9. Applying at least one of the compounds of General formula I according to one of claims 1 to 3 to obtain a medicinal product intended for the treatment or prevention of depression.



 

Same patents:

Indanol derivatives // 2323937

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): (where R1 and R2 may be identical or different, and each is a 1,3-substituted aryl with substituents from group α; R3 stands for any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N(Ra)Rb, -(CH2)m-CO-R5, -(CH2)m-R5, -CO-NH-CO-N(Ra)Rb, -CO-NH-SO2-N(Ra)Rb, -CO-NH-CO-(CH2)m-N(Ra)Rb, or -CO-NH2; R4 stands for a lower alkyl, cycloalkyl, cycloalkyl substituted with 1-3 substituent from group α, lower alkenyl, lower alkynyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl, lower alkoxyalkyl, lower aliphatic acyloxyalkyl or lower alkoxycarbonylalkyl; R5 stands for hydroxyl, -OR4 or -N(Ra)Rb; Rа and Rb may be identical or different, each of them stands for hydrogen, hydroxyl, lower alkoxy group, hydroxyl-substituted lower alkoxyl, hydroxyl-substituted lower alkoxyalkyl, lower alkoxy lower alkoxyalkyl, cyano lower alkyl, cyano lower alkoxyalkyl, carboxy lower alkyl, carboxy lower alkoxyalkyl, aliphatic lower alkoxycarbonyl lower alkoxyalkyl, carbamoyl lower alkyl group, carbamoyl lower alkoxyalkyl, lower aliphatic acylamino lower alkyl, lower aliphatic acylamino lower alkoxyalkyl, lower alkylsulphonylamino lower alkyl, lower alkylsulphanylamino lower alkoxyalkyl, (N-hydroxy-N-methylcarbamoyl) lower alkyl, (N-hydroxy-N-methylcarbamoyl) lower alkoxyalkyl, (N-lower alkoxy-N-methylcarbamoyl) lower alkyl, (N-lower alkoxy-14-methylcarbamoyl) lower alkoxyalkyl or R4, or both, including associated nitrogen, stand for nitrogen-containing heterocyclic group or nitrogen-containing 1-3 substituted heterocyclic group with substituents from group α; m is an integer from 1 to 6; А stands for carbonyl; В stands for straight bond; D stands for oxygen atom; Е stands for С14 alkylene; n is an integer from 1 to 3; and α group is a group of substituents, which consist of halogen atoms, lower alkyls, hydroxy lower alkyls, halogen lower alkyls, carboxy lower alkyls, lower alkoxyls, hydroxy lower alkoxyls, hydroxy lower alkoxyalkyls, lower alkoxycarbonyls, carboxyls, hydroxyls, lower aliphatic acyls, lower aliphatic acylamines, (N-hydroxy-N-methylcarbamoyl) lower alkyls, (N-lower alkoxy-N-methylcarbamoyl) lower alkyls, hydroxy lower aliphatic acylamines, amines, carbamoyls and cyano groups), or pharmacologically suitable salt thereof. Invention also relates to pharmaceutical composition and method for disease prevention and treatment.

EFFECT: preparation of novel biologically active compounds.

18 cl, 117 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

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

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

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

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to nonhygroscopic crystalline 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,2-dimethyl-1H-pyrrol-3-carboxamide maleate salt that possesses inhibitory effect on tyrosine kinase receptors. Also, invention relates to a pharmaceutical composition and to a method for treatment of cancer in mammals using such compositions.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

12 cl, 12 tbl, 17 dwg, 5 ex

FIELD: medicinal chemistry, pharmacy.

SUBSTANCE: invention relates to compounds and pharmaceutical compositions that act as antagonists of metabotropic glutamate receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

7 cl, 3 tbl, 11 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

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

6 cl, 67 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

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

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: substituted 2-pyridyl-1,2-dihydro-4Н-3,1-benzoxazines of formula 1, which activate germination of wheat and exhibit growth-regulating activity, are described. This provides for preparation of novel promising biologically active substances, thus extending the range of growth-regulating compounds in a series of substituted 1,2-dihydro-4Н-3,1-benzoxazines, which improve sowing quality of seeds, providing for sprouts of high vitality resulting in increased potential productivity of sprouts.

1.1 R=Et,

1.2 R=Et,

1.3 R=Ph,

1.4 R=Ph,

EFFECT: provides for preparation of novel chemical substances.

1 tbl, 5 ex

FIELD: medicinal chemistry, pharmacy.

SUBSTANCE: invention relates to compounds and pharmaceutical compositions that act as antagonists of metabotropic glutamate receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

7 cl, 3 tbl, 11 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes using 4,4-diphenyl-3,1-benzoxazino[1,2-c][1,3]benzoxazine of the formula (III) and 4,4-diphenyl-15-nitro-3,1-benzoxazino[1,2-c][1,3]benzoxazine of the formula (IV) wherein in (III) R' means hydrogen atom (H); in (IV) R' means -NO2 as antidotes of herbicide 2,4-dichlorophenoxyacetic acid exerting the hormonal effect for protection of sunflower seedlings. Invention provides expanding spectrum in using the known compounds among substituted 1,2-dihydro-4H-3,1-benzoxazines, namely, their using as antidotes providing decrease of negative effect of herbicide with the hormonal effect for protection of sunflower.

EFFECT: valuable properties of compounds.

2 tbl, 1 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes using 2-(3-nitrophenyl)-4,4-dipgenyl-1,2-dihydro-4H-3,1-benzoxazine of the formula (III) 2-(3-nitro-2-bromophenyl)-4,4-dimethyl-1,2-dihydro-4H-3,1-benzoxazine of the formula (IV) 2-(5-methylfur-2-yl)-4,4-dimethyl-1,2-dihydro-4H-3,1-benzoxazine of the formula (V) as antidotes of herbicide 2,4-dichlorophenoxyacetic acid that exert the hormonal effect for protection of sunflower seedlings. Invention provides expanding spectrum in using the known compounds among substituted 1,2-dihydro-4H-3,1-benzoxazines, namely, their using as antidotes providing decrease of negative effect of herbicide with hormonal effect for protection of sunflower.

EFFECT: valuable properties of compounds.

2 tbl, 1 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to using 4,4-diethyl-1,2-dihydro-4H-3,1-naphthoxazine 0f the formula (III) , 4,4-diphenyl-3,1-benzoxazino[1,2-c][1,3]naphthoxazine of the formula (IV) , 4,4-diphenyl-11-methyl-3,1-benzoxazino[1,2-c][1,3]naphthoxazine of the formula (V) and 4,4-diethyl-3,1-benzoxazino[1,2-c][1,3]naphthoxazine of the formula (VI) wherein in (IV) R means phenyl (Ph), R1 means hydrogen atom (H); in (V) R means -Ph, R1 means -CH3; in (VI) R means -C2H5, R1 means H. These compounds are used as antidotes of herbicide 2,4-dichlorophenylacetic acid that exert the hormonal effect for protection of sunflower seedlings. Invention expands spectrum in using the known compounds among substituted 1,2-dihydro-4H-3,1-benzoxazines, namely, their using as antidotes providing decrease of negative effect of herbicide with hormonal effect for protection of sunflower.

EFFECT: valuable properties of compounds.

2 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-hetaryl-substituted derivatives of 1,2-tropolones of the general formula (Ia): wherein R1 and R2 mean (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl, nitro-group; Het means six-membered nitrogen heterocycle condensed with one or two benzyl rings that can be substituted with substitutes chosen from group comprising halogen atom, nitro-group, (C1-C6)-alkyl, oxy-(C1-C6)-alkyl, secondary amino-group chosen from anilino-, substituted anilino-, hydroxyethylamino-group, or tertiary amino-group chosen from morpholino-, piperidino-, piperazino-group, 1H-1-imidazolyl. Also, invention relates to a method for synthesis of 2-hetaryl-substituted derivatives of 1,3-tropolone. Method involves condensation of benzoquinones-1,2 with 2-methylheterocycles at heating in the presence of acetic acid taken in the amount providing its role as both a catalyst and a solvent. Also, invention relates to a pharmaceutical composition with antibacterial effect based on 2-hetaryl-substituted derivatives of 1,3-tropolone.

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

9 cl, 5 tbl, 3 ex

FIELD: organic chemistry, medicine, endocrinology, biochemistry, pharmacy.

SUBSTANCE: invention relates to 5-substituted pyrazine or pyridine derivatives of the general formula (I): or their pharmaceutically acceptable salts wherein R1 means lower alkyl comprising from 1 to 5 carbon atoms; R2 means hydrogen atom or halogen atom; R3 means cycloalkyl comprising from 4 to 6 carbon atoms; Y means -CH or nitrogen atom (N); R4 means a substitute at position 5 of pyridine or pyrazine ring chosen from group comprising compounds of the following formulae:

Compounds of the formula (I) are activators of glucokinase and can be used in treatment of diabetes mellitus of type II. Also, invention describes a pharmaceutical composition based on proposed compounds and their using in preparing a drug designated for treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

78 cl, 86 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a compound of the formula (I): , wherein carbon atom designated as * is in (R)- or (S)-configuration; R1 represents (C1-C6)-alkyl; R2 represents hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-halogenalkyl; R3 represents H or halogen atom; R4 represents phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl wherein R4 group is substituted optionally with 1-4 R14-substitutes; each among R5, R6 and R7 is chosen independently from the following group: H, halogen atom, -OR11, -CN, (C1-C4)-halogenalkyl or (C1-C6)-alkyl; or R5 and R6 taken in common can represent -O-C-(R12)2-O-; R8 represents H; R11 represents H or (C1-C4)-alkyl; R12 represents (C1-C4)-alkyl; R12 is chosen independently in each case from a substitute chosen from the following group: halogen atom, -OR11, -NR11R12, morpholinyl, (C1-C6)-alkyl and (C1-C4)-halogenalkyl, or its pharmaceutically acceptable salt or solvate. Also, invention describes a pharmaceutical composition used in blocking in reuptake of norepinephrine, dopamine and serotonin based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties, improved method of treatment.

39 cl, 2 tbl, 49 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention covers new compounds of formula I or its salts suitable for pharmacology: , where R1 is selected from phenyl, pyridyl, thienyl, difurylglyoxal, imidazolyl, pyrrolyl and thiazolyl; R2, R3 and R4 independently are d-zalkyl or halogenated C1-zalkyl; and R5 is hydrogen. And also new intermediate compounds formula III: , where R2, R3 and R4 independently are C1-3alkyl or halogenated C1-6alkyl; and R5 is hydrogen. Invention also covers method of production of compound formula I and their applications.

EFFECT: production of new biologically active compounds.

12 cl, 9 ex, 2 tbl

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